Author Report for: Kumar ANo contact information in database for Kumar A
Abdullaha M, Banoo R, Nuthakki VK, Sharma M, Kaur S, Thakur S, Kumar A, Jadhav HR, Bharate SB Ref: ACS Omega, 8:17591, 2023 : PubMed ESTHER: Abdullaha_2023_ACS.Omega_8_17591 PubMedSearch: Abdullaha 2023 ACS.Omega 8 17591 PubMedID: 37251153 Abstract The multifaceted nature of Alzheimer's disease (AD) indicates the need for multitargeted agents as potential therapeutics. Both cholinesterases (ChEs), acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), play a vital role in disease progression. Thus, inhibiting both ChEs is more beneficial than only one for effectively managing AD. The present study provides a detailed lead optimization of the e-pharmacophore-generated pyridinium styryl scaffold to discover a dual ChE inhibitor. A structure-activity relationship analysis indicated the importance of three structural fragments, methoxy-naphthyl, vinyl-pyridinium, and substituted-benzyl, in a dual ChE inhibitor pharmacophore. The optimized 6-methoxy-naphthyl derivative, 7av (SB-1436), inhibits EeAChE and eqBChE with IC(50) values of 176 and 370 nM, respectively. The kinetic study has shown that 7av inhibits AChE and BChE in a non-competitive manner with k(i) values of 46 and 115 nM, respectively. The docking and molecular dynamics simulation demonstrated that 7av binds with the catalytic and peripheral anionic sites of AChE and BChE. Compound 7av also significantly stops the self-aggregation of Abeta. The data presented herein indicate the potential of 7av for further investigation in preclinical models of AD. Title: Cell wall and immune modulation by Rv1800 (PPE28) helps M. smegmatis to evade intracellular killing Anand PK, Saini V, Kaur J, Kumar A Ref: Int J Biol Macromol, :125837, 2023 : PubMed ESTHER: Anand_2023_Int.J.Biol.Macromol__125837 PubMedSearch: Anand 2023 Int.J.Biol.Macromol 125837 PubMedID: 37455004 Gene_locus related to this paper: myctu-Rv1800 Abstract Rv1800 is predicted as PPE family protein found in pathogenic mycobacteria only. Under acidic stress, the rv1800 gene was expressed in M. tuberculosis H37Ra. In-silico study showed lipase/esterase activity in C-terminus PE-PPE domain having pentapeptide motif with catalytic Ser-Asp-His residue. Full-length Rv1800 and C-terminus PE-PPE domain proteins showed esterase activity with pNP-C4 at the optimum temperature of 40 degreesC and pH 8.0. However, the N-terminus PPE domain showed no esterase activity, but involved in thermostability of Rv1800 full-length protein. M. smegmatis expressing rv1800 (MS_Rv1800) showed altered colony morphology and a significant resistance to numerous environmental stresses, antibiotics and higher lipid content. In extracellular and membrane fraction, Rv1800 protein was detected, while C terminus PE-PPE was present in cytoplasm, suggesting the role of N-terminus PPE domain in transportation of protein. MS_Rv1800 infected macrophage showed higher intracellular survival and low production of ROS, NO and expression levels of iNOS and pro-inflammatory cytokines, while induced expression of the anti-inflammatory cytokines. The Rv1800, PPE and PE-PPE showed antibody-mediated immunity in MDR-TB and PTB patients. Overall, these results confirmed the esterase activity in the C-terminus and function of N-terminus in thermostabilization and transportation; predicting the role of Rv1800 in immune/lipid modulation to support intracellular mycobacterium survival. Title: Discovery of Multitarget-Directed Ligands from Piperidine Alkaloid Piperine as a Cap Group for the Management of Alzheimer's Disease Bhanukiran K, Singh SK, Singh R, Kumar A, Hemalatha S Ref: ACS Chem Neurosci, :, 2023 : PubMed ESTHER: Bhanukiran_2023_ACS.Chem.Neurosci__ PubMedSearch: Bhanukiran 2023 ACS.Chem.Neurosci PubMedID: 37433759 Abstract The naturally inspired multitarget-directed ligands (PC01-PC10 and PD01-PD26) were synthesized from piperine for the management of Alzheimer's disease (AD). The compound PD07 showed significant inhibitory activity on ChEs, BACE1, and Abeta(1-42) aggregation in in vitro studies. Further, compound PD07 effectively displaced the propidium iodide at the AChE PAS site. The compound PD07 exhibited significant lipophilicity in PAMPA studies. Additionally, PD07 demonstrated neuroprotective properties in the Abeta(1-42) induced SH-SY5Y cell line. Furthermore, DFT calculations were performed using B3LYP/6-311G(d,p) basis sets to explore the PD07 physical and chemical properties. The compound PD07 showed a similar binding interaction profile at active sites of AChE, BuChE, and BACE1 proteins as compared to reference ligands (donepezil, tacrine, and BSD) in molecular docking and dynamic simulation studies. In acute oral toxicity studies, compound PD07 exhibited no toxicity symptoms up to 300 mg/kg, po. The compound PD07 (10 mg/kg, po) improved memory and cognition in scopolamine-induced amnesia rats. Further, PD07 increased ACh levels in the brain by inhibiting the AChE activity. The results from in vitro, in silico, and in vivo studies suggested that compound PD07 is a potent multitarget-directed lead from piperine to overcome Alzheimer's disease. Title: The role of astrocytic alpha7 nicotinic acetylcholine receptors in Alzheimer disease Fontana IC, Kumar A, Nordberg A Ref: Nat Rev Neurol, :, 2023 : PubMed ESTHER: Fontana_2023_Nat.Rev.Neurol__ PubMedSearch: Fontana 2023 Nat.Rev.Neurol PubMedID: 36977843 Abstract The ongoing search for therapeutic interventions in Alzheimer disease (AD) has highlighted the complexity of this condition and the need for additional biomarkers, beyond amyloid-beta (Abeta) and tau, to improve clinical assessment. Astrocytes are brain cells that control metabolic and redox homeostasis, among other functions, and are emerging as an important focus of AD research owing to their swift response to brain pathology in the initial stages of the disease. Reactive astrogliosis - the morphological, molecular and functional transformation of astrocytes during disease - has been implicated in AD progression, and the definition of new astrocytic biomarkers could help to deepen our understanding of reactive astrogliosis along the AD continuum. As we highlight in this Review, one promising biomarker candidate is the astrocytic alpha7 nicotinic acetylcholine receptor (alpha7nAChR), upregulation of which correlates with Abeta pathology in the brain of individuals with AD. We revisit the past two decades of research into astrocytic alpha7nAChRs to shed light on their roles in the context of AD pathology and biomarkers. We discuss the involvement of astrocytic alpha7nAChRs in the instigation and potentiation of early Abeta pathology and explore their potential as a target for future reactive astrocyte-based therapeutics and imaging biomarkers in AD. Title: Adsorption Characterization of Lactobacillus sp. for Di-(2-ethylhexyl) phthalate Goyal SP, Agarwal T, Mishra V, Kumar A, Saravanan C Ref: Probiotics Antimicrob Proteins, :, 2023 : PubMed ESTHER: Goyal_2023_Probiotics.Antimicrob.Proteins__ PubMedSearch: Goyal 2023 Probiotics.Antimicrob.Proteins PubMedID: 36995550 Abstract Di-(2-ethylhexyl) phthalate (DEHP) is the widely detected plasticizer in foods whose exposure is associated with a myriad of human disorders. The present study focused on identifying Lactobacillus strains with high adsorption potential towards DEHP and further elucidating the mechanism of binding using HPLC, FTIR and SEM. Two strains, Lactobacillus rhamnosus GG and Lactobacillus plantarum MTCC 25,433, were found to rapidly adsorb more than 85% of DEHP in 2 h. Binding potential remained unaffected by heat treatment. Moreover, acid pre-treatment enhanced the DEHP adsorption. Chemical pre-treatments, such as NaIO(4), pronase E or lipase, caused reduction in DEHP adsorption to 46% (LGG), 49% (MTCC 25,433) and 62% (MTCC 25,433), respectively, attributing it to cell wall polysaccharides, proteins and lipids. This was also corroborated by stretching vibrations of C = O, N-H, C-N and C-O functional groups. Furthermore, SDS and urea pre-treatment, demonstrated the crucial role of hydrophobic interactions in DEHP adsorption. The extracted peptidoglycan from LGG and MTCC 25,433 adsorbed 45% and 68% of DEHP, respectively, revealing the imperative role of peptidoglycan and its integrity in DEHP adsorption. These findings indicated that DEHP removal was based on physico-chemical adsorption and cell wall proteins, polysaccharides or peptidoglycan played a primary role in its adsorption. Owing to the high binding efficiency, L. rhamnosus GG and L. plantarum MTCC 25,433 were considered to be a potential detoxification strategy to mitigate the risk associated with the consumption of DEHP-contaminated foods. Title: Ameliorating the Role of Aripiprazole in Memory Deficits Induced by Intracerebroventricular Streptozotocin-Induced Dementia of Alzheimer's Type Gupta T, Singh V, Hefnawy M, Alanazi MM, Alsuwayt B, Kabra A, Kumar A, Pasricha C, Singh R Ref: ACS Omega, 8:25295, 2023 : PubMed ESTHER: Gupta_2023_ACS.Omega_8_25295 PubMedSearch: Gupta 2023 ACS.Omega 8 25295 PubMedID: 37483219 Abstract Alzheimer's disease (AD) is a progressive neurodegenerative disorder causing immense suffering for the patients. Dopamine D2 and 5-hydroxytryptamine receptor 1A (5-HT1A) receptors' activation has been reported to play a crucial role in managing neurological outcomes in the brain and other health disorders. This study aimed to investigate the role of aripiprazole, a dopamine D2 and 5-HT1A selective receptors' activator, in the restoration of memory deficit induced by streptozotocin in mice. The cognitive functions of animals were determined using the Morris water maze. Brain sections were stained with hematoxylin and eosin and Congo red to examine the structural deviations. Brain oxidative stress (thiobarbituric acid reactive substance and glutathione), acetylcholinesterase activity, IL-6, and IL-10 were measured to assess biochemical alterations. Activation of D2 and 5-HT1A with aripiprazole attenuated STZ-induced cognitive deficit, increased brain GSH levels, reduced TBARS levels, AChE activity, IL-6 levels, and IL-10 levels and prevented STZ-induced brain anomalies in mice. Hence, the present study concluded that aripiprazole mitigated STZ-induced memory impairment and can be used as an efficacious therapeutic target for the management of AD. Title: Discovery of triazole-bridged aryl adamantane analogs as an intriguing class of multifunctional agents for treatment of Alzheimer's disease Gutti G, Leifeld J, Kakarla R, Bajad NG, Ganeshpurkar A, Kumar A, Krishnamurthy S, Klein-Schmidt C, Tapken D and Singh SK <1 more author(s)> Gutti G, Leifeld J, Kakarla R, Bajad NG, Ganeshpurkar A, Kumar A, Krishnamurthy S, Klein-Schmidt C, Tapken D, Hollmann M, Singh SK (- 1) Ref: Eur Journal of Medicinal Chemistry, 259:115670, 2023 : PubMed ESTHER: Gutti_2023_Eur.J.Med.Chem_259_115670 PubMedSearch: Gutti 2023 Eur.J.Med.Chem 259 115670 PubMedID: 37515920 Inhibitor(s) related to this paper: triazole-aryl-adamantane-Cpd32 Abstract Alzheimer's disease (AD) is a progressive brain disorder associated with slow loss of brain functions leading to memory failure and modest changes in behavior. The multifactorial neuropathological condition is due to a depletion of cholinergic neurons and accumulation of amyloid-beta (Abeta) plaques. Recently, a multi-target-directed ligand (MTDL) strategy has emerged as a robust drug discovery tool to overcome current challenges. In this research work, we aimed to design and develop a library of triazole-bridged aryl adamantane analogs for the treatment of AD. All synthesized analogs were characterized and evaluated through various in vitro and in vivo biological studies. The optimal compounds 32 and 33 exhibited potent inhibitory activities against acetylcholinesterase (AChE) (32 - IC(50) = 0.086 microM; 33 - 0.135 microM), and significant Abeta aggregation inhibition (20 microM). N-methyl-d-aspartate (NMDA) receptor (GluN1-1b/GluN2B subunit combination) antagonistic activity of compounds 32 and 33 measured upon heterologous expression in Xenopus laevis oocytes showed IC(50) values of 3.00 microM and 2.86 microM, respectively. The compounds possessed good blood-brain barrier permeability in the PAMPA assay and were safe for SH-SY5Y neuroblastoma (10 microM) and HEK-293 cell lines (30 microM). Furthermore, in vivo behavioral studies in rats demonstrated that both compounds improved cognitive and spatial memory impairment at a dose of 10 mg/kg oral administration. Together, our findings suggest triazole-bridged aryl adamantane as a promising new scaffold for the development of anti-Alzheimer's drugs. Title: Industrial applications of fungal lipases: a review Kumar A, Verma V, Dubey VK, Srivastava A, Garg SK, Singh VP, Arora PK Ref: Front Microbiol, 14:1142536, 2023 : PubMed ESTHER: Kumar_2023_Front.Microbiol_14_1142536 PubMedSearch: Kumar 2023 Front.Microbiol 14 1142536 PubMedID: 37187537 Abstract Fungal lipases (triacylglycerol acyl hydrolases EC 3.1.1.3) are significant industrial enzymes and have several applications in a number of industries and fields. Fungal lipases are found in several species of fungi and yeast. These enzymes are carboxylic acid esterases, categorized under the serine hydrolase family, and do not require any cofactor during the catalyzing of the reactions. It was also noticed that processes including the extraction and purification of lipases from fungi are comparatively easier and cheaper than other sources of lipases. In addition, fungal lipases have been classified into three chief classes, namely, GX, GGGX, and Y. Fungal lipases have applications not only in the hydrolysis of fats and oils (triglycerides) but are also involved in synthetic reactions such as esterification, acidolysis, alcoholysis, interesterification, and aminolysis. The production and activity of fungal lipases are highly affected by the carbon source, nitrogen source, temperature, pH, metal ions, surfactants, and moisture content. Therefore, fungal lipases have several industrial and biotechnological applications in many fields such as biodiesel production, ester synthesis, production of biodegradable biopolymers, formulations of cosmetics and personal care products, detergent manufacturing, degreasing of leather, pulp and paper production, textile industry, biosensor development, and drug formulations and as a diagnostic tool in the medical sector, biodegradation of esters, and bioremediation of wastewater. The immobilization of fungal lipases onto different carriers also helps in improving the catalytic activities and efficiencies of lipases by increasing thermal and ionic stability (in organic solvents, high pH, and temperature), being easy to recycle, and inducing the volume-specific loading of the enzyme onto the support, and thus, these features have proved to be appropriate for use as biocatalysts in different sectors. Title: Effect of Curcumin and Coenzyme Q10 Alone and in Combination on Learning and Memory in an Animal Model of Alzheimer's Disease Kumar P, Singh A, Kumar A, Kumar R, Pal R, Sachan AK, Dixit RK, Nath R Ref: Biomedicines, 11:, 2023 : PubMed ESTHER: Kumar_2023_Biomedicines_11_ PubMedSearch: Kumar 2023 Biomedicines 11 PubMedID: 37239093 Abstract The most frequent neurodegenerative illness among senior people and the main cause of dementia is Alzheimer's disease. The present dementia medications available only help with the symptoms of cognitive deficits and have several negative effects. The current study's goal is to assess the effects of curcumin and coenzyme Q10, two herbal medicines, both separately and in combination, on learning and memory before comparing them to the industry standard drug. A total of 42 adult healthy Wistar rats were used in our study. In this experiment, rats were given daily doses of 2.5 mg/kg of body weight of scopolamine hydrobromide for 7 days to induce Alzheimer's disease. On the eighth day, behavioural testing was conducted. Following testing, scopolamine and the test medications were given daily for the following 21 days. On days 29 and 30, behavioural testing was conducted once more, and then animals were slaughtered. Brain homogenate was produced for the estimation of molecular and biochemical markers. Curcumin has demonstrated a dose-response relationship, with a higher dose (200 mg/kg b.w. p.o.) being more effective than a lower dose (100 mg/kg b.w. p.o.). Similar to the greater dose of curcumin, coenzyme Q10 (200 mg/kg b.w. p.o.) has also been found to improve memory and learning. Higher doses of curcumin and coenzyme Q10 had more pronounced and meaningful effects. Acetylcholinesterase and TNF levels increased in scopolamine-induced memory impairment, but these effects were restored by the test medications, and improved by the combined therapy. These outcomes are comparable to those of the common medication memantine. As a result, we may infer from our results that curcumin at higher doses and its combination with coenzyme Q10 (200 mg/kg b.w. p.o.) have a significant impact on cognitive impairment in animal models of Alzheimer's disease and can be utilised alone or as an add-on therapy for the condition. Title: Targeting DPP4-RBD interactions by sitagliptin and linagliptin delivers a potential host-directed therapy against pan-SARS-CoV-2 infections Mani S, Kaur A, Jakhar K, Kumari G, Sonar S, Kumar A, Das S, Kumar S, Kumar V and Majumdar T <3 more author(s)> Mani S, Kaur A, Jakhar K, Kumari G, Sonar S, Kumar A, Das S, Kumar S, Kumar V, Kundu R, Pandey AK, Singh UP, Majumdar T (- 3) Ref: Int J Biol Macromol, 245:125444, 2023 : PubMed ESTHER: Mani_2023_Int.J.Biol.Macromol_245_125444 PubMedSearch: Mani 2023 Int.J.Biol.Macromol 245 125444 PubMedID: 37385308 Gene_locus related to this paper: human-DPP4 Inhibitor(s) related to this paper: Linagliptin, Sitagliptin Abstract Highly mutated SARS-CoV-2 is known aetiological factor for COVID-19. Here, we have demonstrated that the receptor binding domain (RBD) of the spike protein can interact with human dipeptidyl peptidase 4 (DPP4) to facilitate virus entry, in addition to the usual route of ACE2-RBD binding. Significant number of residues of RBD makes hydrogen bonds and hydrophobic interactions with alpha/beta-hydrolase domain of DPP4. With this observation, we created a strategy to combat COVID-19 by circumventing the catalytic activity of DPP4 using its inhibitors. Sitagliptin, linagliptin or in combination disavowed RBD to establish a heterodimer complex with both DPP4 and ACE2 which is requisite strategy for virus entry into the cells. Both gliptins not only impede DPP4 activity, but also prevent ACE2-RBD interaction, crucial for virus growth. Sitagliptin, and linagliptin alone or in combination have avidity to impede the growth of pan-SARS-CoV-2 variants including original SARS-CoV-2, alpha, beta, delta, and kappa in a dose dependent manner. However, these drugs were unable to alter enzymatic activity of PLpro and Mpro. We conclude that viruses hijack DPP4 for cell invasion via RBD binding. Impeding RBD interaction with both DPP4 and ACE2 selectively by sitagliptin and linagliptin is an potential strategy for efficiently preventing viral replication. Title: Design, Synthesis, and Pharmacological Evaluation of Embelin-Aryl/alkyl Amine Hybrids as Orally Bioavailable Blood-Brain Barrier Permeable Multitargeted Agents with Therapeutic Potential in Alzheimer's Disease: Discovery of SB-1448 Nuthakki VK, Choudhary S, Reddy CN, Bhatt S, Jamwal A, Jotshi A, Raghuvanshi R, Sharma A, Thakur S and Bharate SB <4 more author(s)> Nuthakki VK, Choudhary S, Reddy CN, Bhatt S, Jamwal A, Jotshi A, Raghuvanshi R, Sharma A, Thakur S, Jadhav HR, Bharate SS, Nandi U, Kumar A, Bharate SB (- 4) Ref: ACS Chem Neurosci, :, 2023 : PubMed ESTHER: Nuthakki_2023_ACS.Chem.Neurosci__ PubMedSearch: Nuthakki 2023 ACS.Chem.Neurosci PubMedID: 36812360 Abstract The complex and multifaceted nature of Alzheimer's disease has brought about a pressing demand to develop ligands targeting multiple pathways to combat its outrageous prevalence. Embelin is a major secondary metabolite of Embelia ribes Burm f., one of the oldest herbs in Indian traditional medicine. It is a micromolar inhibitor of cholinesterases (ChEs) and beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1) with poor absorption, distribution, metabolism, and excretion (ADME) properties. Herein, we synthesize a series of embelin-aryl/alkyl amine hybrids to improve its physicochemical properties and therapeutic potency against targeted enzymes. The most active derivative, 9j (SB-1448), inhibits human acetylcholinesterase (hAChE), human butyrylcholinesterase (hBChE), and human BACE-1 (hBACE-1) with IC(50) values of 0.15, 1.6, and 0.6 microM, respectively. It inhibits both ChEs noncompetitively with k(i) values of 0.21 and 1.3 microM, respectively. It is orally bioavailable, crosses blood-brain barrier (BBB), inhibits Abeta self-aggregation, possesses good ADME properties, and protects neuronal cells from scopolamine-induced cell death. The oral administration of 9j at 30 mg/kg attenuates the scopolamine-induced cognitive impairments in C57BL/6J mice. Title: Structure-based Virtual Screening and Molecular Dynamic Simulation Approach for the Identification of Terpenoids as Potential DPP-4 Inhibitors P AA, Kumar A, Jangid K, Kumar V, Jaitak V Ref: Curr Comput Aided Drug Des, :, 2023 : PubMed ESTHER: P_2023_Curr.Comput.Aided.Drug.Des__ PubMedSearch: P 2023 Curr.Comput.Aided.Drug.Des PubMedID: 37190809 Abstract BACKGROUND: Diabetes mellitus is a metabolic disorder where insulin secretion is compromised, leading to hyperglycemia. DPP-4 is a viable and safer target for type 2 diabetes mellitus. Computational tools have proven to be an asset in the process of drug discovery. OBJECTIVE: In the present study, tools like structure-based virtual screening, MM/GBSA, and pharmacokinetic parameters were used to identify natural terpenoids as potential DPP-4 inhibitors for treating diabetes mellitus. METHODS: Structure-based virtual screening, a cumulative mode of elimination technique, was adopted, identifying the top five potent hit compounds depending on the docking score and non-bonding interactions. RESULTS: According to the docking data, the most important contributors to complex stability are hydrogen bonding, hydrophobic interactions, and Pi-Pi stacking interactions. The dock scores ranged from -6.492 to -5.484 kcal/mol, indicating robust ligand-protein interactions. The pharmacokinetic characteristics of top-scoring hits (CNP0309455, CNP0196061, CNP0122006, CNP0221869, CNP0297378) were also computed in this study, confirming their safe administration in the human body. Also, based on the synthetic accessibility score, all top-scored hits are easily synthesizable. Compound CNP0309455 was quite stable during molecular dynamic simulation studies. CONCLUSION: Virtual database screening yielded new leads for developing DPP-4 inhibitors. As a result, the findings of this study can be used to design and develop natural terpenoids as DPP-4 inhibitors for the medication of diabetes mellitus. Title: Exploring Potent Fungal Isolates from Sanitary Landfill Soil for In Vitro Degradation of Dibutyl Phthalate Puranik S, Shukla L, Kundu A, Kamil D, Paul S, Venkadasamy G, Salim R, Singh SK, Kumar D, Kumar A Ref: J Fungi (Basel), 9:, 2023 : PubMed ESTHER: Puranik_2023_J.Fungi.(Basel)_9_ PubMedSearch: Puranik 2023 J.Fungi.(Basel) 9 PubMedID: 36675946 Abstract Di-n-butyl phthalate (DBP) is one of the most extensively used plasticizers for providing elasticity to plastics. Being potentially harmful to humans, investigating eco-benign options for its rapid degradation is imperative. Microbe-mediated DBP mineralization is well-recorded, but studies on the pollutant's fungal catabolism remain scarce. Thus, the present investigation was undertaken to exploit the fungal strains from toxic sanitary landfill soil for the degradation of DBP. The most efficient isolate, SDBP4, identified on a molecular basis as Aspergillus flavus, was able to mineralize 99.34% dibutyl phthalate (100 mg L(-1)) within 15 days of incubation. It was found that the high production of esterases by the fungal strain was responsible for the degradation. The strain also exhibited the highest biomass (1615.33 mg L(-1)) and total soluble protein (261.73 microg mL(-1)) production amongst other isolates. The DBP degradation pathway scheme was elucidated with the help of GC-MS-based characterizations that revealed the formation of intermediate metabolites such as benzyl-butyl phthalate (BBP), dimethyl-phthalate (DMP), di-iso-butyl-phthalate (DIBP) and phthalic acid (PA). This is the first report of DBP mineralization assisted with A. flavus, using it as a sole carbon source. SDBP4 will be further formulated to develop an eco-benign product for the bioremediation of DBP-contaminated toxic sanitary landfill soils. Title: 2D-QSAR, molecular docking and MD simulation based virtual screening of the herbal molecules against Alzheimer's disorder: an approach to predict CNS activity Thakur A, Sharma B, Parashar A, Sharma V, Kumar A, Mehta V Ref: J Biomol Struct Dyn, :1, 2023 : PubMed ESTHER: Thakur_2023_J.Biomol.Struct.Dyn__1 PubMedSearch: Thakur 2023 J.Biomol.Struct.Dyn 1 PubMedID: 36970779 Abstract Acetylcholinesterase (AChE) is one of the key enzyme targets that have been used clinically for the management of Alzheimer's Disorder (AD). Numerous reports in the literature predict and demonstrate in-vitro, and in-silico anticholinergic activity of herbal molecules, however, majority of them failed to find clinical application. To address these issues, we developed a 2D-QSAR model that could efficiently predict the AChE inhibitory activity of herbal molecules along with predicting their potential to cross the blood-brain-barrier (BBB) to exert their beneficial effects during AD. Virtual screening of the herbal molecules was performed and amentoflavone, asiaticoside, astaxanthin, bahouside, biapigenin, glycyrrhizin, hyperforin, hypericin, and tocopherol were predicted as the most promising herbal molecules for inhibiting AChE. Results were validated through molecular docking, atomistic molecular dynamics simulations and Molecular mechanics-Poisson Boltzmann surface area (MM-PBSA) studies against human AChE (PDB ID: 4EY7). To determine whether or not these molecules can cross BBB to inhibit AChE within the central nervous system (CNS) for being beneficial for the management of AD, we determined a CNS Multi-parameter Optimization (MPO) score, which was found in the range of 1 to 3.76. Overall, the best results were observed for amentoflavone and our results demonstrated a PIC(50) value of 7.377 nM, molecular docking score of -11.5 kcal/mol, and CNS MPO score of 3.76. In conclusion, we successfully developed a reliable and efficient 2D-QSAR model and predicted amentoflavone to be the most promising molecule that could inhibit human AChE enzyme within the CNS and could prove beneficial for the management of AD.Communicated by Ramaswamy H. Sarma. Title: A Mild Dose of Aspirin Promotes Hippocampal Neurogenesis and Working Memory in Experimental Ageing Mice Vergil Andrews JF, Selvaraj DB, Kumar A, Roshan SA, Anusuyadevi M, Kandasamy M Ref: Brain Sci, 13:, 2023 : PubMed ESTHER: Vergil_2023_Brain.Sci_13_ PubMedSearch: Vergil 2023 Brain.Sci 13 PubMedID: 37509038 Abstract Aspirin has been reported to prevent memory decline in the elderly population. Adult neurogenesis in the hippocampus has been recognized as an underlying basis of learning and memory. This study investigated the effect of aspirin on spatial memory in correlation with the regulation of hippocampal neurogenesis and microglia in the brains of ageing experimental mice. Results from the novel object recognition (NOR) test, Morris water maze (MWM), and cued radial arm maze (cued RAM) revealed that aspirin treatment enhances working memory in experimental mice. Further, the co-immunohistochemical assessments on the brain sections indicated an increased number of doublecortin (DCX)-positive immature neurons and bromodeoxyuridine (BrdU)/neuronal nuclei (NeuN) double-positive newly generated neurons in the hippocampi of mice in the aspirin-treated group compared to the control group. Moreover, a reduced number of ionized calcium-binding adaptor molecule (Iba)-1-positive microglial cells was evident in the hippocampus of aspirin-treated animals. Recently, enhanced activity of acetylcholinesterase (AChE) in circulation has been identified as an indicative biomarker of dementia. The biochemical assessment in the blood of aspirin-treated mice showed decreased activity of AChE in comparison with that of the control group. Results from this study revealed that aspirin facilitates hippocampal neurogenesis which might be linked to enhanced working memory. Title: Environment dependent expression of mycobacterium hormone sensitive lipases: expression pattern under ex-vivo and individual in-vitro stress conditions in M. tuberculosis H37Ra Arya S, Singh P, Kaur J, Kumar A Ref: Mol Biol Rep, :, 2022 : PubMed ESTHER: Arya_2022_Mol.Biol.Rep__ PubMedSearch: Arya 2022 Mol.Biol.Rep PubMedID: 35301657 Abstract BACKGROUND: Hormone-sensitive lipase (HSL) is a neutral lipase capable of hydrolysing various kinds of lipids. In comparison to single human Hormone Sensitive Lipase (hHSL), that is induced under nutritional stress, twelve serine hydrolases are annotated as HSL in Mycobacterium tuberculosis (mHSL). Mycobacterium is exposed to multiple stresses inside the host. Therefore, the present study was carried out to investigate if mHSL are also expressed under stress condition and if there is any correlation between various stress conditions and expression pattern of mHSL. METHODS AND RESULTS: The expression pattern of mHSL under different environmental conditions (in-vitro and ex-vivo) were studied using qRT-PCR in M. tuberculosis H37Ra strain with 16 S rRNA as internal control. Out of 12, only two genes (lipU and lipY) were expressed at very low level in mid log phase culture under aerobic conditions, while 9 genes were expressed at stationary phase of growth. Ten mHSLs were expressed post-infection under ex-vivo conditions in time dependent manner. LipH and lipQ did not express at any time point under ex-vivo condition. The relative expression of most of the genes under individual stress was much higher than observed in ex-vivo conditions. The expression pattern of genes varied with change in stress condition. CONCLUSIONS: Different sets of mHSL genes were expressed under different individual stress conditions pointing towards the requirement of different mHSL to combat different stress conditions. Overall, most of the mHSLs have demonstrated stress dependent expression pointing towards their role in intracellular survival of mycobacteria. Title: Structural Insight of New Butyrylcholinesterase Inhibitors Based on Benzylbenzofuran Scaffold Delogu GL, Fais A, Pintus F, Goyal C, Matos MJ, Era B, Kumar A Ref: Pharmaceuticals (Basel), 15:, 2022 : PubMed ESTHER: Delogu_2022_Pharmaceuticals.(Basel)_15_ PubMedSearch: Delogu 2022 Pharmaceuticals.(Basel) 15 PubMedID: 35337102 Abstract In the present work, we use a merger of computational and biochemical techniques as a rational guideline for structural modification of benzofuran derivatives to find pertinent structural features for the butyrylcholinesterase inhibitory activity and selectivity. Previously, we revealed a series of 2-phenylbenzofuran compounds that displayed a selective inhibitory activity for BChE. Here, in an effort to discover novel selective BChE inhibitors with favorable physicochemical and pharmacokinetic profiles, 2-benzylbenzofurans were designed, synthesized, and evaluated as BChE inhibitors. The 2-phenylbenzofuran scaffold structure is modified by introducing one methylene spacer between the benzofuran core and the 2-phenyl ring with a hydroxyl substituent in the para or meta position. Either position 5 or 7 of the benzofuran scaffold was substituted with a bromine or chlorine atom. Further assessment of the selected list of compounds indicated that the substituent's nature and position determined their activity and selectivity. 5-bromo-2-(4-hydroxybenzyl)benzofuran 9B proved to be the most potent butyrylcholinesterase inhibitor (IC(50) = 2.93 microM) of the studied series. Computational studies were carried out to correlate the theoretical and experimental binding affinity of the compounds to the BChE protein. Title: Identification of sulfonamide based butyrylcholinesterase inhibitors through scaffold hopping approach Ganeshpurkar A, Singh R, Kumar D, Gore P, Shivhare S, Sardana D, Rayala S, Kumar A, Singh SK Ref: Int J Biol Macromol, :, 2022 : PubMed ESTHER: Ganeshpurkar_2022_Int.J.Biol.Macromol__ PubMedSearch: Ganeshpurkar 2022 Int.J.Biol.Macromol PubMedID: 35090939 Abstract Butyrylcholinesterase (BChE), a hydrolytic enzyme, is responsible for the termination of the action of acetylcholine besides acetylcholinesterase (AChE) in the synaptic cleft of the brain. The alteration in the enzyme level, in patients with the progression of Alzheimer's disease, makes it a therapeutic target. In the present study, we developed BChE inhibitors through scaffold hopping by exploring two previously reported compounds, i.e., 1,4-bis((4-chlorophenyl) sulfonyl)-3,6-diphenylpiperazine-2,5-dione and N-(2-chlorophenyl)-4-(phenylsulfonamido)benzamide, to afford scaffold and pharmacophore fragments, respectively. The N,2-diphenyl-2-(phenylsulfonamido)acetamide derivatives, thus designed, were synthesised and screened for the inhibition of AChE and BChE enzymes. Compounds 30 and 33 were found to be most active against BChE among the derivatives, with IC(50) values of 7.331 +/- 0.946 and 10.964 +/- 0.936 microM, respectively. The compounds displayed a non-competitive mode of inhibition along with BBB permeability and good cell viability on SH-SY5Y cell line. The molecular docking analysis of the compounds with BChE showed interactions with Trp82, Trp231, Leu286, and His438. The molecular dynamics study revealed the stability of the protein-ligand complexes. Title: Identification of sulfonamide-based butyrylcholinesterase inhibitors using machine learning Ganeshpurkar A, Singh R, Kumar D, Gutti G, Gore P, Sahu B, Kumar A, Singh SK Ref: Future Med Chem, :, 2022 : PubMed ESTHER: Ganeshpurkar_2022_Future.Med.Chem__ PubMedSearch: Ganeshpurkar 2022 Future.Med.Chem PubMedID: 35707942 Abstract Aim: This study reports the designing of BChE inhibitors through machine learning (ML), followed by in silico and in vitro evaluations. Methodology: ML technique was used to predict the virtual hit, and its derivatives were synthesized and characterized. The compounds were evaluated by using various in vitro tests and in silico methods. Results: The gradient boosting classifier predicted N-phenyl-4-(phenylsulfonamido) benzamide as an active BChE inhibitor. The derivatives of the inhibitor, i.e., compounds 34, 37 and 54 were potent BChE inhibitors and displayed blood-brain barrier permeability with no significant AChE inhibition. Conclusion: The ML prediction was effective, and the synthesized compounds showed the BChE inhibitory activity, which was also supported by the in silico studies. Title: Identification of potential AChE inhibitors through combined machine-learning and structure-based design approaches Ganeshpurkar A, Singh R, Singh RB, Kumar D, Kumar A, Singh SK Ref: Indian J Biochem Biophys, 59:619, 2022 : PubMed ESTHER: Ganeshpurkar_2022_Indian.J.Biochem.Biophys_59_619 PubMedSearch: Ganeshpurkar 2022 Indian.J.Biochem.Biophys 59 619 Abstract Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative disease characterised by dementia.The depletion of acetylcholine (ACh) is involved the synaptic cleft is responsible for dementia due to neuronal loss. The acetylcholinesterase (AChE) enzyme isinvolved in the hydrolytic degradation of ACh and its inhibition is therapeutically beneficial for the treatment in memory loss.The use of machine learning (ML) for the identification of enzyme inhibitors has recently become popular. It identifies important patterns in the reported inhibitors to predict the new molecules. Hence, in this study, a set of support vector classifier-based ML models were developed,validated and employed to predict AChE inhibitors. Further, 247 predicted compounds obtained through PAINS and molecular property filters were docked on the AChE enzyme. The docking study identified compounds AAM132011183, ART21232619 and LMG16204648 as AChE inhibitors with suitable ADME properties. The selected compounds produced stable interactions with enzymes in molecular dynamics studies. The novel inhibitors obtained from the study may be proposed as active leads for AChE inhibition. Title: Design, synthesis, extra-precision docking, and molecular dynamics simulation studies of pyrrolidin-2-one derivatives as potential acetylcholinesterase inhibitors Gupta M, Kumar A, Prasun C, Nair MS, Kini SG, Yadav D, Nain S Ref: J Biomol Struct Dyn, :1, 2022 : PubMed ESTHER: Gupta_2022_J.Biomol.Struct.Dyn__1 PubMedSearch: Gupta 2022 J.Biomol.Struct.Dyn 1 PubMedID: 35921217 Abstract Inhibition of acetylcholinesterase (AChE) has been widely explored to develop novel molecules for management of Alzheimer's disease. In past research finding reported molecule 3-(4-(4-fluorobenzoyl)piperidin-1-yl)-1-(4-methoxybenzyl)pyrrolidin-2-one displayed a spectrum of anti-Alzheimer's properties herein, we report a library of 18 novel molecules that were rationally designed and synthesized employing known literature to mimic and explore the novel chemical space around the lead compound 6e and donepezil. All the compounds were docked in extra-precision mode with AChE (PDB ID 4EY7) using the Glide module. Molecular dynamics (MD) simulation studies were carried out for 100 ns along with MM-PBSA studies of the trajectory frames generated post-MD simulations. Docking and MD simulation studies suggested that the synthesized compounds showed a good binding affinity with AChE. and might form stable complexes. 3-(4-(benzyl(methyl)amino)piperidin-1-yl)-1-(3,4-dimethoxybenzyl)pyrrolidin-2-one (14a; docking score: -18.59) and 1-(3,4-dimethoxybenzyl)-3-(4-(methyl(thiazol-2-ylmethyl)amino)piperidin-1-yl)pyrrolidin-2-one (14d; docking score: -18.057) showed higher docking score than donepezil (docking score: -17.257) while most of the compounds had docking score >-10.0. ADMET study predicted these compounds to be CNS active and most of the compounds were drug-like molecules with no HERG blockade and good to excellent oral absorption. We developed an atom-based 3 D-QSAR model with R^2 and Q^2 values of 0.9639 and 0.8779 to predict the activity of the synthesized compounds. The model predicted these compounds to be potent AChE inhibitors with IC(50) values in the lower micromolar range. Based on the in silico findings, we report these newly synthesized compounds 3-(4-(benzyl(methyl)amino)piperidin-1-yl)-1-(3,4-dimethoxybenzyl)pyrrolidin-2-one (14a) and 7-(2,6-difluorobenzyl)-2-(4-methoxybenzyl)-2,7-diazaspiro[4.5]decan-1-one (20 b) as potential AChE inhibitors.Communicated by Ramaswamy H. Sarma. Title: A Recent Appraisal of Small-Organic Molecules as Anti-Alzheimer's Agents Gupta M, Kumar A, Ojha M, Khan SK, Nain S Ref: Mini Rev Med Chem, :, 2022 : PubMed ESTHER: Gupta_2022_Mini.Rev.Med.Chem__ PubMedSearch: Gupta 2022 Mini.Rev.Med.Chem PubMedID: 36154572 Abstract BACKGROUND: Alzheimer's disease (AD) is an irreversible, progressive and very complex brain disorder. There is still uncertainty around the etiology of AD, but a few hallmarks like an aggregation of tau proteins, amyloid-beta plaques, oxidative stress, low level of choline in the brain etc. play significant roles. OBJECTIVE: In the present work, we aim to evaluate the recent progress in the development of small organic molecules containing heterocycles like thiazole, pyridines, dihydropyridines, piperidines, pyrrolidines, pyrazoles, quinolines etc. as anti-Alzheimer's agents. METHOD: Several databases of different journal publications SciFinder, Science Direct, Bentham Science, and Pubmed were searched for relevant articles and reviewed for the present work. RESULTS: Several research groups are actively working on these heterocycle-based compounds as potent single-target inhibitors. Most of the analogues have been evaluated for their cholinesterase (acetylcholinesterase and butyrylcholinesterase) inhibition potential. Several studies have also reported the inhibitory potential of the analogues against MAO-A, MAO-B and BACE-1 enzymes. But nowadays instead of targeting one enzyme or protein, more than one heterocycle ring is being joined to develop MTDLs (multi-target-directed ligands). Especially, donepezil has become the focal point of anti-AD drug discovery projects. Several research groups have reported various donepezil-based analogues by replacing/modifying its various ring systems like indanone, piperidine or the methylene linker. CONCLUSION: Small molecules with nitrogen-containing heterocycles have become the core of drug discovery efforts for AD. With the increasing prominence of the MTDL approach, several new ligands are being discovered as potent anti-AD agents. Title: Dental pulp stem cell secretome ameliorates d-galactose induced accelerated aging in rat model Kumar A, Mahajan A, Kumari P, Singh J, Raik S, Saha L, Pal A, Medhi B, Rattan V, Bhattacharyya S Ref: Cell Biochemistry & Function, :, 2022 : PubMed ESTHER: Kumar_2022_Cell.Biochem.Funct__ PubMedSearch: Kumar 2022 Cell.Biochem.Funct PubMedID: 35790015 Abstract Advancing age is associated with several diseases and disorders due to multiorgan atrophy. The increasing proportion of elderly humans demands the identification of means to counteract aging and age-associated disorders. There is an increased depletion of stem cells in the aged organs, resulting in their inability to repair the damage and hence organ degeneration. Stem cell therapy has been implicated in counteracting aging and shown promise. However, the use of stem cells encounters several side effects and complications such as handling and storage of the cells for transplantation purpose. Stem cells secretome has proven to be of significant importance in a variety of disorders. In this study, we have shown that secretome derived from dental pulp stem cells (DPSCs) can reverse the age-associated degeneration induced by chronic exposure to d-galactose in a rat model. The secretome was able to increase muscle grip strength and animal activity. Secretome also improved the kidney function and hepatic biochemistry similar to healthy controls as evaluated by renal function test and Fourier-transform infrared spectroscopy. We also showed that secretome reduced the levels of monoamine oxidase and acetylcholinesterase in the brain and liver, indicating aging reversal. Finally, proteomic profiling of DPSCs secretome revealed the presence of 13 proteins which have antiaging functions. Thus, our study provides first proof of concept that DPSCs secretome can render protection against d-galactose induced accelerated aging. Title: Recent advances in the development of nitrogen-containing heterocyclic Anti-Alzheimer's agents Kumar A, Nehra B, Singh D, Kuma D, Chawla PA Ref: Curr Top Med Chem, :, 2022 : PubMed ESTHER: Kumar_2022_Curr.Top.Med.Chem__ PubMedSearch: Kumar 2022 Curr.Top.Med.Chem PubMedID: 36278462 Abstract Alzheimer's disease (AD) remains one of the major neurodegenerative diseases overwhelming the world today. Alzheimer's is the most complicated as well as perplexing disease encountering serious global health issues. Alzheimer's disease is well characterized as a general cause of dementia, which includes issues with memory, language, problem-solving, and other cognitive behaviours, such as disabled perception as well as trouble talking due to degeneration of neurons. According to the latest report, there are about 44 million individuals who are currently suffering from dementia, which has been prophesied to extensively grow up to 3-fold by 2050. Alzheimer's disease is usually triggered by numerous associated factors, including depleted amount of acetylcholine (ACh), excessive aggregation of beta-amyloid peptide (Abeta), tau hyperphosphorylation with neurofibrillary tangle formation as well as deposition of feeble plaques in a specific portion of the brain (hippocampus and cortex). Besides these superior factors, sometimes AD can be induced or become complex due to several reasons, such as inflammatory mechanisms and oxidative stress. Furthermore, heterocyclic scaffolds comprise assorted implications in the drug design and development process. Heterocycles have also elicited their evolving role as core scaffolds in numerous synthetic derivatives with potent anti-Alzheimer's potential. There are only limited drugs that are present in the market to treat Alzheimer's disease in an efficacious manner. Hence, the identification, design, and development of new anti-Alzheimer's drugs is therefore an emerging need to eradicate complex clinical indications associated with Alzheimer's disease. This review aims to summarize various recent advancements in the medicinal chemistry of heterocycle-based compounds with the following objectives: (1) To represent inclusive literature reports describing the anti-Alzheimer's potential of heterocyclic derivatives; (2) To cast light on recent advancements in the medicinal chemistry of heterocyclic compounds endowed with their therapeutic potential against Alzheimer's disease; (3) To summarize the comprehensive correlation of structure-activity relationship (SAR) with the pharmacological responses, including in silico and mechanistic studies to provide ideas related to design and development of lead molecules. Title: An overview of the pharmacological activities of scopoletin against different chronic diseases Parama D, Girisa S, Khatoon E, Kumar A, Alqahtani MS, Abbas M, Sethi G, Kunnumakkara AB Ref: Pharmacol Res, 179:106202, 2022 : PubMed ESTHER: Parama_2022_Pharmacol.Res_179_106202 PubMedSearch: Parama 2022 Pharmacol.Res 179 106202 PubMedID: 35378275 Abstract Chronic diseases are considered a major public health concern worldwide, and most of these diseases like cancer, cardiovascular, metabolic, and neurological disorders occur due to atypical regulation of multiple signaling pathways. It has also been observed that most of the currently approved therapies for these diseases fail to show prolonged efficacy due to their mono-targeted nature and are associated with the development of chemoresistance, thus restricting their utility. The plant-derived compounds, on the other hand, show multi-targeted nature, and thus these phytochemicals have gained wide attention as they offer negligible side effects. The present review aims to recapitulate the potential effects of one such phytochemical, Scopoletin, which was found to have a diverse range of pharmacological activities such as anti-cancer, anti-diabetic, anti-inflammatory, cardioprotective, hepatoprotective, etc. Scopoletin modulated multiple molecular signatures in cancer, including AMPK, EGFR, MAPK/ ERK, NF-kappaB, PI3K/Akt/ mTOR, and STAT3; regulated the levels of critical markers of metabolic diseases such as ALT, AST, TG, and TC; inflammatory diseases such as ILs and TNFs; neurological diseases such as AChE, etc. thus relieving the symptoms and severity associated with these diseases. Further, this compound has a non-toxic nature and possesses an excellent pharmacokinetic property, which warrants further investigation in clinical settings for developing it as a potential drug. Title: Recent advances in assessment methods and mechanism of microbe-mediated chlorpyrifos remediation Raj A, Kumar A Ref: Environ Research, :114011, 2022 : PubMed ESTHER: Raj_2022_Environ.Res__114011 PubMedSearch: Raj 2022 Environ.Res 114011 PubMedID: 35985484 Abstract Chlorpyrifos (CP) is one of the Organophosphorus pesticides (OPs) primarily used in agriculture to safeguard crops from pests and diseases. The pervasive use of chlorpyrifos is hazardous to humans and the environment as it inhibits the receptor for acetylcholinesterase activity, leading to abnormalities linked to the central nervous system. Hence, there is an ardent need to develop an effective and sustainable approach to the on-site degradation of chlorpyrifos. The role of microbes in the remediation of pesticides is considered the most effective and eco-friendly approach, as they have strong degradative potential due to their gene and enzymes naturally adapted to these sites. Several reports have previously been published on exploring the role of microbes in the degradation of CP. However, detection of CP as an environmental contaminant is an essential prerequisite for developing an efficient microbial-mediated biodegradation method with less harmful intermediates. Most of the articles published to date discuss the fate and impact of CP in the environment along with its degradation mechanism but still fail to discuss the analytical portion. This review is focused on the latest developments in the field of bioremediation of CP along with its physicochemical properties, toxicity, fate, and conventional (UV-Visible spectrophotometer, FTIR, NMR, GC-MS, etc) and advanced detection methods (Biosensors and immunochromatography-based methods) from different environmental samples. Apart from it, this review explores the role of metagenomics, system biology, in-silico tools, and genetic engineering in facilitating the bioremediation of CP. One of the objectives of this review is to educate policymakers with scientific data that will enable the development of appropriate strategies to reduce pesticide exposure and the harmful health impacts on both Human and other environmental components. Moreover, this review provides up-to-date developments related to the sustainable remediation of CP. Title: Mixture toxicity assessment of selected insecticides to silver perch fingerling, Bidyanus bidyanus Arora S, Kumar A Ref: Ecotoxicology & Environmental Safety, 226:112790, 2021 : PubMed ESTHER: Arora_2021_Ecotoxicol.Environ.Saf_226_112790 PubMedSearch: Arora 2021 Ecotoxicol.Environ.Saf 226 112790 PubMedID: 34653840 Abstract The organophosphorus (OP) and carbamate (CB) insecticides are responsible for inhibition of the Acetylcholinesterase (AChE) enzyme. The AChE activity, therefore, has been demonstrated to be a potent biomarker for these insecticides in terrestrial and aquatic environments. The objective of this study was to investigate the response of AChE in the brain of four-week old fingerlings of silver perch, Bidyanus bidyanus exposed to OP and CB insecticides. The fish fingeling were exposed to three OPs and one CB insecticide as individual and their binary mixtures for 48 h. The OP insecticides with oxon (PO) as well as thion (PS) group gets oxidized to oxon analogs in biological systems. The 50% AChE inhibition (48 h EC(50)) in fingerling exposed to chlorpyrifos (CPF) and triazophos (TRZ) was evident at 2.3 and 6.7 microg/L, respectively. The toxicological interaction of three OPs and one CB insecticide was evaluated using the toxic unit method. A strong synergism was observed for binary combination of CPF with profenofos (PRF), and CPF with TAZ. In contrast, the mixture of TAZ with PRF and carbofuran (CBF) with CPF and PRF showed antagonistic behavior. Although OP and CB insecticides can break down rapidly in the environment, this study suggests that non-target aquatic biota may be exposed to mixtures of ChE-inhibiting insecticides for a period of several months, in agricultural regions where insecticides are applied for extended periods of the year. And at environmentally relevant concentrations such mixtures may lead to deleterious effects in non-target organisms. Title: A systematic review of carbohydrate-based bioactive molecules for Alzheimer's disease Bajad NG, Swetha R, Gutti G, Singh M, Kumar A, Singh SK Ref: Future Med Chem, :, 2021 : PubMed ESTHER: Bajad_2021_Future.Med.Chem__ PubMedSearch: Bajad 2021 Future.Med.Chem PubMedID: 34472382 Abstract The abundance, low cost, high density of functional groups and ease of purification of carbohydrates are among the most important features that make them a prime candidate for designing therapeutics. Several carbohydrate-based molecules, of both natural and synthetic origin, are known for their wide range of therapeutic activities. The incorporation of a carbohydrate moiety not only retains the pharmacological characteristics of a molecule but also improves its activity. Several sugar conjugates have been designed and reported to inhibit acetylcholinesterase, beta-amyloid and tau aggregation. This systematic review provides a brief overview of carbohydrate-based bioactive molecules having anti-Alzheimer's activity along with improved therapeutic potential. Most importantly, several reported carbohydrate-based molecules for Alzheimer's disease act on beta-amyloid aggregation, tau protein, cholinesterase and oxidative stress, with enhanced pharmacokinetic and mechanistic properties. The prospect of designing carbohydrate-based molecules for Alzheimer's disease will definitely provide potential opportunities to discover novel carbohydrate-based drugs. Title: Deciphering the Behavioral Response of Meloidogyne incognita and Fusarium oxysporum Toward Mustard Essential Oil Dutta A, Mandal A, Kundu A, Malik M, Chaudhary A, Khan MR, Shanmugam V, Rao U, Saha S and Singh A <5 more author(s)> Dutta A, Mandal A, Kundu A, Malik M, Chaudhary A, Khan MR, Shanmugam V, Rao U, Saha S, Patanjali N, Kumar R, Kumar A, Dash S, Singh PK, Singh A (- 5) Ref: Front Plant Sci, 12:714730, 2021 : PubMed ESTHER: Dutta_2021_Front.Plant.Sci_12_714730 PubMedSearch: Dutta 2021 Front.Plant.Sci 12 714730 PubMedID: 34512695 Abstract Environmental concerns related to synthetic pesticides and the emphasis on the adoption of an integrated pest management concept as a cardinal principle have strengthened the focus of global research and development on botanical pesticides. A scientific understanding of the mode of action of biomolecules over a range of pests is key to the successful development of biopesticides. The present investigation focuses on the in silico protein-ligand interactions of allyl isothiocyanate (AITC), a major constituent of black mustard (Brassica nigra) essential oil (MEO) against two pests, namely, Meloidogyne incognita (Mi) and Fusarium oxysporum f. sp. lycopersici (Fol), that cause severe yield losses in agricultural crops, especially in vegetables. The in vitro bioassay results of MEO against Mi exhibited an exposure time dependent on the lethal concentration causing 50% mortality (LC(50)) values of 47.7, 30.3, and 20.4 microg ml(-1) at 24, 48, and 72 h of exposure, respectively. The study revealed short-term nematostatic activity at lower concentrations, with nematicidal activity at higher concentrations upon prolonged exposure. Black mustard essential oil displayed excellent in vitro Fol mycelial growth inhibition, with an effective concentration to cause 50% inhibition (EC(50)) value of 6.42 microg ml(-1). In order to decipher the mechanism of action of MEO, its major component, AITC (87.6%), which was identified by gas chromatography-mass spectrometry (GC-MS), was subjected to in silico docking and simulation studies against seven and eight putative target proteins of Mi and Fol, respectively. Allyl isothiocyanate exhibited the highest binding affinity with the binding sites of acetyl cholinesterase (AChE), followed by odorant response gene-1 (ODR1) and neuropeptide G-protein coupled receptor (nGPCR) in Mi, suggesting the possible suppression of neurotransmission and chemosensing functions. Among the target proteins of Fol, AITC was the most effective protein in blocking chitin synthase (CS), followed by 2,3-dihydroxy benzoic acid decarboxylase (6m53) and trypsinase (1try), thus inferring these as the principal molecular targets of fungal growth. Taken together, the study establishes the potential of MEO as a novel biopesticide lead, which will be utilized further to manage the Mi-Fol disease complex. Title: Identification of 1,2,4-triazolylthioethanone Scaffold for the Design of New Acetylcholinesterase Inhibitors Fatiha Muhammad E, Kumar A, Wahab HA, Zhang KYJ Ref: Mol Inform, :, 2021 : PubMed ESTHER: Fatiha_2021_Mol.Inform__ PubMedSearch: Fatiha 2021 Mol.Inform PubMedID: 34060234 Abstract Acetylcholinesterase (AChE) inhibitors are the most effective drugs for Alzheimer's disease treatment. However, considering the potential and failure rates of AChE inhibitors, chemical scaffolds targeting cholinesterase specifically are still very limited. Herein, we report a new class of AChE inhibitors identified by employing a virtual screening approach that combines shape similarity with molecular docking calculations. Virtual screening followed by the evaluation of AChE inhibitory activity allowed us to identify 1,2,4-triazolylthioethanones as a novel class of AChE inhibitors. Thirteen compounds with 1,2,4-triazolylthiothanone core and IC(50) values in the range of 0.15+/-0.07 to 3.32+/-0.92microM have been reported here. Our findings shed light into a class of AChE inhibitors that could be useful starting point for the development of novel therapeutics to tackle Alzheimer's disease. Title: Washingtonia filifera seed extracts inhibit the islet amyloid polypeptide fibrils formations and alpha-amylase and alpha-glucosidase activity Floris S, Fais A, Medda R, Pintus F, Piras A, Kumar A, Kus PM, Westermark GT, Era B Ref: J Enzyme Inhib Med Chem, 36:517, 2021 : PubMed ESTHER: Floris_2021_J.Enzyme.Inhib.Med.Chem_36_517 PubMedSearch: Floris 2021 J.Enzyme.Inhib.Med.Chem 36 517 PubMedID: 33494628 Abstract Washingtonia filifera seeds have revealed to possess antioxidant properties, butyrylcholinesterase and xanthine oxidase inhibition activities. The literature has indicated a relationship between Alzheimer's disease (AD) and type-2 diabetes (T2D). Keeping this in mind, we have now evaluated the inhibitory properties of W. filifera seed extracts on alpha-amylase, alpha-glucosidase enzyme activity and the Islet Amyloid Polypeptide (IAPP) fibrils formation. Three extracts from seeds of W. filifera were evaluated for their enzyme inhibitory effect and IC(50) values were calculated for all the extracts. The inhibition mode was investigated by Lineweaver-Burk plot analysis and the inhibition of IAPP aggregate formation was monitored. W. filifera methanol seed extract appears as the most potent inhibitor of alpha-amylase, alpha-glucosidase, and for the IAPP fibril formation. Current findings indicate new potential of this extract that could be used for the identification or development of novel potential agents for T2D and AD. Title: Improved machine learning scoring functions for identification of Electrophorus electricus's acetylcholinesterase inhibitors Ganeshpurkar A, Singh R, Shivhare S, Divya, Kumar D, Gutti G, Kumar A, Singh SK Ref: Mol Divers, :, 2021 : PubMed ESTHER: Ganeshpurkar_2021_Mol.Divers__ PubMedSearch: Ganeshpurkar 2021 Mol.Divers PubMedID: 34328603 Abstract Structure-based drug design (SBDD) is an important in silico technique, used for the identification of enzyme inhibitors. Acetylcholinesterase (AChE), obtained from Electrophorus electricus (ee), is widely used for the screening of AChE inhibitors. It shares structural homology with the AChE of human and other organisms. Till date, the three-dimensional crystal structure of enzyme from ee is not available that makes it challenging to use the SBDD approach for the identification of inhibitors. A homology model was developed for eeAChE in the present study, followed by its structural refinement through energy minimisation. The docking protocol was developed using a grid dimension of 84 x 66 x 72 and grid point spacing of 0.375 A for eeAChE. The protocol was validated by redocking a set of co-crystallised inhibitors obtained from mouse AChE, and their interaction profiles were compared. The results indicated a poor performance of the Autodock scoring function. Hence, a batch of machine learning-based scoring functions were developed. The validation results displayed an accuracy of 81.68 +/- 1.73% and 82.92 +/- 3.05% for binary and multiclass classification scoring function, respectively. The regression-based scoring function produced [Formula: see text] and [Formula: see text] values of 0.94, 0.635 and 0.634, respectively. Title: Development of homology model, docking protocol and Machine-Learning based scoring functions for identification of Equus caballus's butyrylcholinesterase inhibitors Ganeshpurkar A, Singh R, Kumar D, Gutti G, Sardana D, Shivhare S, Singh RB, Kumar A, Singh SK Ref: J Biomol Struct Dyn, :1, 2021 : PubMed ESTHER: Ganeshpurkar_2021_J.Biomol.Struct.Dyn__1 PubMedSearch: Ganeshpurkar 2021 J.Biomol.Struct.Dyn 1 PubMedID: 34696689 Abstract Machine learning (ML), an emerging field in drug design, has the potential to predict in silico toxicity, shape-based analysis of inhibitors, scoring function (SF) etc. In the present study, a homology model, docking protocol, and a dedicated SF have been developed to identify the inhibitors of horse butyrylcholinesterase (BChE) enzyme. Horse BChE enzyme has homology with human BChE and is a substitute for the screening of in vitro inhibitors. The developed homology model was validated and the active site residues were identified from Cavityplus to generate grid box for docking. The validation of docking involved comparison of interactions of ligands co-crystallised with human BChE and the docked poses of the corresponding ligands with horse BChE. A high degree of similarity in the interaction profiles of generated poses validated the docking protocol. Scoring of ligands was further validated by docking with known BChE inhibitors. The binding energies obtained from SF was correlated with IC(50) values of inhibitors through classification and regression-based methods, which indicated poor predictivity of native SF. Therefore, protein-ligand binding energy, interaction profile, and ligand descriptors were used to develop and validate the classification and regression-based models. The validated extra tree binary classifier, random forest and extra tree regression-based models were compiled as a protein-ligand SF and were made available to the users through web application and python library. ML models exhibited improved area under the curve for ROC and good correlation between the predicted and observed IC(50) values, than the Autodock SF.Communicated by Ramaswamy H. Sarma. Title: Design, Synthesis, biological investigations and molecular interactions of triazole linked tacrine glycoconjugates as Acetylcholinesterase inhibitors with reduced hepatotoxicity Kaur Gulati H, Choudhary S, Kumar N, Ahmed A, Bhagat K, Vir Singh J, Singh A, Kumar A, Singh Bedi PM and Mukherjee D <1 more author(s)> Kaur Gulati H, Choudhary S, Kumar N, Ahmed A, Bhagat K, Vir Singh J, Singh A, Kumar A, Singh Bedi PM, Singh H, Mukherjee D (- 1) Ref: Bioorg Chem, 118:105479, 2021 : PubMed ESTHER: Kaur_2021_Bioorg.Chem_118_105479 PubMedSearch: Kaur 2021 Bioorg.Chem 118 105479 PubMedID: 34801945 Abstract Tacrine is a known Acetylcholinesterase (AChE) inhibitors having hepatotoxicity as main liability associated with it. The present study aims to reduce its hepatotoxicity by synthesizing tacrine linked triazole glycoconjugates via Huisgen's [3 + 2] cycloaddition of anomeric azides and terminal acetylenes derived from tacrine. A series of triazole based glycoconjugates containing both acetylated (A-1 to A-7) and free sugar hydroxyl groups (A-8 to A-14) at the amino position of tacrine were synthesized in good yield taking aid from molecular docking studies and evaluated for their in vitro AChE inhibition activity as well as hepatotoxicity. All the hybrids were found to be non-toxic on HePG2 cell line at 200 microM (100 % cell viability) as compared to tacrine (35 % cell viability) after 24 h of incubation period. Enzyme kinetic studies carried out for one of the potent hybrids in the series A-1 (IC(50) 0.4 microM) revealed its mixed inhibition approach. Thus, compound A-1 can be used as principle template to further explore the mechanism of action of different targets involved in Alzheimer's disease (AD) which stands as an adequate chemical probe to be launched in an AD drug discovery program. Title: Biomedical Implications of Plant-Based Principles as Antidepressants: Prospects for Novel Drug Development Khushboo, Kumar A, Sharma B Ref: Mini Rev Med Chem, :, 2021 : PubMed ESTHER: Khushboo_2021_Mini.Rev.Med.Chem__ PubMedSearch: Khushboo 2021 Mini.Rev.Med.Chem PubMedID: 33858313 Abstract BACKGROUND: Depression is a most common mental disorder. The symptoms of depression include loss of energy, changes in appetite, more or less sleep, anxiety, low concentration, uncertainty, restlessness, feelings of worthlessness, guilt, or despair, and thoughts of self-harm or suicide. In order to provide safe, efficient and cost-effective medication, the plants based principles in isolation or in combination with traditional antidepressants are attracting increasing attention for depression therapy. METHOD: The information regarding the present review and its contents such as collected from published literature materials in different international journals. We have used different search engines such as PubMed, Medline, ResearchGate Google Semantic Scholar and ScienceDirect. For this purpose, the data obtained were properly organized and suitably analyzed to include in this article. RESULTS: Most of the phytomolecules isolated from the medicinal plants display antidepressant effect through the synaptic regulation of levels of neurotransmitters such as dopamine, serotonin, and noradrenaline in different parts of the brain. The mechanism of action of phytomolecules also involves negative regulation of the activities of monoamine oxidase (MAO) and acetylcholinesterase (AChE) and prevention of hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis. In addition, the strong antioxidative and antiinflamatory potential of these phytochemicals offer synergy to their antidepressant as well as antipsychosomatic functions. CONCLUSION: The application of phytochemicals has proved it to be a safe, cost effective and efficient therapeutic agent to treat the patients suffering from mild to severe state of depression and other psychiatric disorders. The potential phytochemicals may be further optimized using in silico tools to develop better antidepressants and antisychotic agents in future. Title: Pancreatic lipase inhibitors: The road voyaged and successes Kumar A, Chauhan S Ref: Life Sciences, :119115, 2021 : PubMed ESTHER: Kumar_2021_Life.Sci__119115 PubMedSearch: Kumar 2021 Life.Sci 119115 PubMedID: 33515565 Abstract Human pancreatic lipase (triacylglycerol acyl hydrolase EC3.1.1.3) is the most widely studied member of the human lipase superfamily related to carboxyl esterase. It is secreted from the acinar cell of pancreas and has strong preference for triacylglycerides over cholesterol esters, phospholipids, and galactolipids. Apart from the hydrolysis of triacylglycerides, pancreatic lipase may cause the hydrolysis of retinyl esters in vivo. So, it is very much evidenced that pancreatic lipase with its cofactor colipase has prominent role in efficient digestion of dietary fat. Hence, the modulation of human pancreatic lipase may represent a new insight in the discovery of a number of therapeutics that can inhibit the absorption of fat in body and can be used in obesity and other related metabolic disorders. Even, the only Food and drug administration (FDA) approved antiobesity drug, orlistat, is also an inhibitor of pancreatic lipase. This review summarizes studies about structure, mechanistic approach of pancreatic lipase enzyme while emphasizing on the various synthetic pancreatic lipase inhibitors with their structure activity relationship (SAR). Title: Arbutin attenuates monosodium L-glutamate induced neurotoxicity and cognitive dysfunction in rats Kumar M, Kumar A, Sindhu RK, Kushwah AS Ref: Neurochem Int, 151:105217, 2021 : PubMed ESTHER: Kumar_2021_Neurochem.Int_151_105217 PubMedSearch: Kumar 2021 Neurochem.Int 151 105217 PubMedID: 34710534 Abstract Excitotoxicity, oxidative stress, and neuro-inflammation underlie the pathogenesis of neurodegenerative brain disorders. Although L-glutamate is the prime excitatory neurotransmitter involved in diverse brain functions, however, overabundance at synapse can activate cell death mechanisms. Previous studies indicate that arbutin affords relief in metabolic, cardiovascular, and gastrointestinal disorders. Recently, arbutin showed benefits in animal models of epilepsy, Parkinson's disease, and Alzheimer's disease that further expanded its therapeutic potential against brain disorders. In the present study, we aimed to evaluate the potential of arbutin against monosodium L-glutamate (MSG) neurotoxicity in rats. Wistar rats (male, 180-200 g) were administered MSG (4 mg/kg) and arbutin (50 and 100 mg/kg) intraperitoneally for 21 days. Cognitive functions were assessed using elevated plus maze and novel object recognition task. Biochemical parameters of oxidative stress, tumour necrosis factor-alpha (TNF-alpha), gamma-amino butyric acid (GABA), acetylcholinesterase (AChE) activity, lactate dehydrogenase (LDH), and intracellular cation-levels (Na(+), Ca(2+), K(+)) were determined using whole brain. Administration of MSG augmented cation-levels, oxidative stress, inflammation, AChE, and LDH activities, and decreased GABA levels in the brain. Arbutin (50 and 100 mg/kg, i.p.) significantly decreased these biochemical disturbances in the brain of MSG administered rats. Behavioural results showed that MSG triggered cognitive deficits in rats that were significantly attenuated by arbutin. Histopathological findings in hippocampus and cortex revealed neuroprotective outcome of arbutin treatments against MSG. MK-801 and N((G))-nitro-L-arginine methyl ester (L-NAME) enhanced memory and neuroprotective effects in rats treated with arbutin and MSG. Arbutin may afford therapeutic advantages in neurodegenerative brain disorders by suppressing the excitotoxic pathways. Title: The lipolytic activity of LipJ, a stress-induced enzyme, is regulated by its C-terminal adenylate cyclase domain Kumari B, Kaur J, Maan P, Kumar A Ref: Future Microbiol, :, 2021 : PubMed ESTHER: Kumari_2021_Future.Microbiol__ PubMedSearch: Kumari 2021 Future.Microbiol PubMedID: 33960821 Abstract Aim: The confirmation of lipolytic activity and role of Rv1900c in the mycobacterium physiology Methods: rv1900c/N-terminus domain (rv1900NT) were cloned in pET28a/Escherichia coli, purified by affinity chromatography and characterized. Results: A zone of clearance on tributyrin-agar and activity with pNP-decanoate confirmed the lipolytic activity of Rv1900c. The Rv1900NT demonstrated higher enzyme specific activity, V(max) and k(cat), but Rv1900c was more thermostable. The lipolytic activity of Rv1900c decreased in presence of ATP. Mycobacterium smegmatis expressing rv1900c/rv1900NT altered colony morphology, growth, cell surface properties and survival under stress conditions. The effect was more prominent with Rv1900NT as compared with Rv1900c. Conclusion: The study confirmed the lipolytic activity of Rv1900c and suggested its regulation by the adenylate cyclase domain and role in intracellular survival of bacteria. Title: Partially saturated canthaxanthin alleviates aging-associated oxidative stress in D-galactose administered male wistar rats Mathimaran A, Kumar A, Prajapati G, Ampapathi RS, Bora HK, Guha R Ref: Biogerontology, 22:19, 2021 : PubMed ESTHER: Mathimaran_2021_Biogerontology_22_19 PubMedSearch: Mathimaran 2021 Biogerontology 22 19 PubMedID: 32926226 Abstract It has been earlier reported that partially saturated canthaxanthin (PSC) from Aspergillus carbonarius mutant is non-toxic, has anti-lipid peroxidation activity and can induce apoptosis in prostate cancer cell lines. In the present study, the antiaging effect of PSC was explored in D-galactose administered male wistar rats. 8-10 weeks old, male wistar rats were randomly divided into (i) Vehicle Control Group (VCG), (ii) Aged Control Group (ACG), (iii) Aged+alpha Lipoic Acid Group (ALG) and (iv) Aged+Partially saturated canthaxanthin Group (APG). Rats received D-galactose (300 mg /kg bwt/day; i.p.) alone (ACG) or together with PSC (APG) (20 mg/kg bwt/day; oral) and alpha Lipoic Acid (ALG) (80 mg/kg bwt/day; oral) for 10 weeks. Rats in VCG were injected with the same volume of physiological saline (i.p.) and fed with olive oil (vehicle). In vitro protein oxidation and DNA oxidation inhibition, in vivo malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), acetylcholinesterase (AChE) and monoamine oxidase (MAO) activities were determined. In addition, brain neurotransmitters, dopamine and serotonin were estimated by NMR. PSC treatment showed inhibition against protein and DNA oxidation. PSC effectively improved D-galactose induced aging rats by inducing a protective effect through up-regulation of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), catalase (CAT) and brain neurotransmitters and downregulated malondialdehyde (MDA) and monoamineoxidase (MAO) levels. Thus, PSC appears to be a functional compound having antioxidant and antiaging properties. Title: Pharmacological investigations on efficacy of Phlorizin a sodium-glucose co-transporter (SGLT) inhibitor in mouse model of intracerebroventricular streptozotocin induced dementia of AD type Rani R, Kumar A, Jaggi AS, Singh N Ref: J Basic Clin Physiol Pharmacol, :, 2021 : PubMed ESTHER: Rani_2021_J.Basic.Clin.Physiol.Pharmacol__ PubMedSearch: Rani 2021 J.Basic.Clin.Physiol.Pharmacol PubMedID: 33548170 Abstract OBJECTIVES: The study has been commenced to discover the potential of Phlorizin (dual SGLT inhibitor) in streptozotocin induced dementia of Alzheimer's disease (AD) type. MATERIAL AND METHODS: Injection of Streptozotocin (STZ) was given via i.c.v. route (3 mg/kg) to induce dementia of Alzheimer's type. In these animals learning and memory was evaluated using Morris water maze (MWM) test. Glutathione (GSH) and thiobarbituric acid reactive species (TBARS) level was quantified to evaluate the oxidative stress; cholinergic activity of brain was estimated in term of acetylcholinesterase (AChE) activity; and the levels of myeloperoxidase (MPO) were measured as inflammation marker. RESULTS: The mice model had decreased performance in MWM, representing impairment of cognitive functions. Biochemical evaluation showed rise in TBARS level, MPO and AChE activity, and fall in GSH level. The histopathological study revealed severe infiltration of neutrophils. In the study, Phlorizin/Donepezil (serving as positive control) treatment mitigate streptozotocin induced cognitive decline, histopathological changes and biochemical alterations. CONCLUSIONS: The results suggest that Phlorizin decreased cognitive function via its anticholinesterase, antioxidative, antiinflammatory effects and probably through SGLT inhibitory action. It can be conferred that SGLTs can be an encouraging target for the treatment of dementia of AD. Title: Ameliorative role of rolipram, PDE-4 inhibitor, against sodium arsenite-induced vascular dementia in rats Virk D, Kumar A, Jaggi AS, Singh N Ref: Environ Sci Pollut Res Int, :, 2021 : PubMed ESTHER: Virk_2021_Environ.Sci.Pollut.Res.Int__ PubMedSearch: Virk 2021 Environ.Sci.Pollut.Res.Int PubMedID: 34226994 Abstract Arsenic exposure to the population leads to serious health problems like neurotoxicity, nephrotoxicity, and cardiovascular abnormality. In the present study, the work has been commenced to discover the prospect of rolipram a phosphodiestrase-4 (PDE-4) inhibitor against sodium arsenite (SA)-induced vascular endothelial dysfunction (EnDF) leading to dementia in rats. Wistar rats were treated with SA (5 mg/kg body weight/day orally) for 44 days for induction of vascular EnDF and dementia. Learning and memory were evaluated using Morris water maze (MWM) test. Vascular EnDF was evaluated using aortic ring preparation. Various biochemical parameters were also evaluated like brain oxidative stress (viz. reduced glutathione and thiobarbituric acid reactive substances level), serum nitrite/nitrate activity, acetylcholinesterase activity, and inflammatory markers (viz. neutrophil infiltration in brain and myeloperoxidase). SA-treated rats showed poor performance in water maze trials indicating attenuated memory and ability to learn with significant rise (p < 0.05) in brain acetylcholinesterase activity, brain oxidative stress, neutrophil count, and significant decrease (p < 0.05) in serum nitrite/nitrate levels and vascular endothelial functions. Rolipram (PDE-4 inhibitor) treatment (0.03 mg/kg and 0.06 mg/kg body weight, intraperitoneally daily for 14 days) significantly improved memory and learning abilities, and restored various biochemical parameters and EnDF. It is concluded that PDE-4 modulator may be considered the prospective target for the treatment of SA-induced vascular EnDF and related dementia. Title: Discovery of a New Donepezil-like Acetylcholinesterase Inhibitor for Targeting Alzheimer's Disease: Computational Studies with Biological Validation Akhoon BA, Choudhary S, Tiwari H, Kumar A, Barik MR, Rathor L, Pandey R, Nargotra A Ref: J Chem Inf Model, 60:4717, 2020 : PubMed ESTHER: Akhoon_2020_J.Chem.Inf.Model_60_4717 PubMedSearch: Akhoon 2020 J.Chem.Inf.Model 60 4717 PubMedID: 32955256 Abstract Alzheimer's disorder is one of the most common worldwide health problems, and its prevalence continues to increase, thereby straining the healthcare budgets of both developed and developing countries. So far, donepezil is the only Food and Drug Administration-approved dual-binding site inhibitor of acetylcholinesterase (AChE) that can amplify the cholinergic activity and also decrease Abeta aggregation in Alzheimer patients. We report herein a new donepezil-like natural compound derivative (D1) as a convincing AChE inhibitor. The in silico studies suggests that D1 exhibits a dual-binding mode of action and interacts with both the catalytic anionic site and peripheral anionic site (PAS) of human AChE. The biological studies confirm the dual-binding site character of D1 and revealed that D1 not only enhances the acetylcholine levels but also reduces the accumulation of Abeta plaques in Caenorhabditis elegans. In fact, 5 microM D1 was seen more potent in elevating the acetylcholine expression than 25 microM donepezil. While most of the non-cholinergic functions of donepezil, associated with the PAS of AChE, were gradually lost at higher concentrations, D1 was more functional at similar doses. Promisingly, D1 also exerted an agonistic effect on the alpha7 nicotinic acetylcholine receptor. Title: Computational Studies on Acetylcholinesterase Inhibitors: From Biochemistry to Chemistry Bagri K, Kumar A, Manisha, Kumar P Ref: Mini Rev Med Chem, 20:1403, 2020 : PubMed ESTHER: Bagri_2020_Mini.Rev.Med.Chem_20_1403 PubMedSearch: Bagri 2020 Mini.Rev.Med.Chem 20 1403 PubMedID: 31884928 Abstract Acetylcholinesterase inhibitors are the most promising therapeutics for Alzheimer's disease treatment as these prevent the loss of acetylcholine and slows the progression of the disease. The drugs approved for the management of Alzheimer's disease by the FDA are acetylcholinesterase inhibitors but are associated with side effects. Consistent and stringent efforts by the researchers with the help of computational methods opened new ways of developing novel molecules with good acetylcholinesterase inhibitory activity. In this manuscript, we reviewed the studies that identified the essential structural features of acetylcholinesterase inhibitors at the molecular level as well as the techniques like molecular docking, molecular dynamics, quantitative structure-activity relationship, virtual screening, and pharmacophore modelling that were used in designing these inhibitors. Title: Characterization of the CAZy Repertoire from the Marine-Derived Fungus Stemphylium lucomagnoense in Relation to Saline Conditions Ben Ali W, Navarro D, Kumar A, Drula E, Turbe-Doan A, Correia LO, Baumberger S, Bertrand E, Faulds CB and Record E <3 more author(s)> Ben Ali W, Navarro D, Kumar A, Drula E, Turbe-Doan A, Correia LO, Baumberger S, Bertrand E, Faulds CB, Henrissat B, Sciara G, Mechichi T, Record E (- 3) Ref: Mar Drugs, 18:, 2020 : PubMed ESTHER: Ben Ali_2020_Mar.Drugs_18_ PubMedSearch: Ben Ali 2020 Mar.Drugs 18 PubMedID: 32916905 Abstract Even if the ocean represents a large part of Earth's surface, only a few studies describe marine-derived fungi compared to their terrestrial homologues. In this ecosystem, marine-derived fungi have had to adapt to the salinity and to the plant biomass composition. This articles studies the growth of five marine isolates and the tuning of lignocellulolytic activities under different conditions, including the salinity. A de novo transcriptome sequencing and assembly were used in combination with a proteomic approach to characterize the Carbohydrate Active Enzymes (CAZy) repertoire of one of these strains. Following these approaches, Stemphylium lucomagnoense was selected for its adapted growth on xylan in saline conditions, its high xylanase activity, and its improved laccase activities in seagrass-containing cultures with salt. De novo transcriptome sequencing and assembly indicated the presence of 51 putative lignocellulolytic enzymes. Its secretome composition was studied in detail when the fungus was grown on either a terrestrial or a marine substrate, under saline and non-saline conditions. Proteomic analysis of the four S. lucomagnoense secretomes revealed a minimal suite of extracellular enzymes for plant biomass degradation and highlighted potential enzyme targets to be further studied for their adaptation to salts and for potential biotechnological applications. Title: Correlation and prognostic significance of serum amylase, serum lipase, and plasma cholinesterase in acute organophosphorus poisoning Dungdung A, Kumar A, Kumar B, Preetam M, Tara RK, Saba MK Ref: J Family Med Prim Care, 9:1873, 2020 : PubMed ESTHER: Dungdung_2020_J.Family.Med.Prim.Care_9_1873 PubMedSearch: Dungdung 2020 J.Family.Med.Prim.Care 9 1873 PubMedID: 32670933 Abstract BACKGROUND: Organophosphorus (OP) are substances that are originally produced by the reaction of alcohols and phosphoric acid. These OP compounds are the main components of herbicides, pesticides, and insecticides. These are easily available in developing country like India; there is lack of awareness about these chemicals which results in high morbidity and mortality. AIMS AND OBJECTIVES: To estimate levels of amylase, lipase, plasma cholinesterase in acute OP poisoning. To assess severity of OP poisoning by using plasma cholinesterase levels and correlating it with other two markers. Predicting the severity of acute OP poisoning by using these biochemical markers. MATERIALS AND METHODS: A hospital-based observational study was conducted on 100 subjects who were clinically diagnosed of acute OP poisoning. Subjects of either gender of all age-groups were included in the study. On admission, plasma cholinesterase, serum amylase, and serum lipase were measured. Based on plasma cholinesterase activity at the time of admission, subjects were divided into three groups. Group I-having 20-50% of plasma cholinesterase activity; Group II-10-20% of plasma cholinesterase activity; and Group III <10% of plasma cholinesterase activity. RESULTS: Among 100 patients it was seen that serum amylase and serum lipase were negatively correlated with plasma cholinesterase levels and it was statistically significant. It was seen that serum amylase had the highest diagnostic accuracy for assessing severity of poisoning, 10 deaths were there in which 6 had <10% of plasma cholinesterase activity, 8 out of these 10 patients had elevated amylase level. CONCLUSION: OP poisoning is associated with elevated amylase level. Serum amylase, lipase can be used as an additional prognostic indicator along with plasma cholinesterase levels. Serum amylase could be considered as a better predictor of severity than lipase. Title: Structural and functional insights about unique extremophilic bacterial lipolytic enzyme from metagenome source Kaur R, Kumar R, Verma S, Kumar A, Rajesh C, Sharma PK Ref: Int J Biol Macromol, :, 2020 : PubMed ESTHER: Kaur_2020_Int.J.Biol.Macromol__ PubMedSearch: Kaur 2020 Int.J.Biol.Macromol PubMedID: 32088224 Gene_locus related to this paper: bacce-BC4862 Abstract In the present investigation, a lipid hydrolyzing gene RPK01was cloned from metagenome source of hot spring. Expression and purification of recombinant protein revealed a protein band of ~24 KDa on 12% SDS-PAGE and is well corroborated with the deduced molecular weight calculated from its amino acid sequence. The purified protein displayed high activity towards short chain fatty acids and was found to be completely stable at 30 degrees C till 3h, and retained ~40% activity at 50 degrees C and 60 degrees C temperature till 3h. Additionally, the pH stability assay showed its functionality in broad range pH, with maximum stability observed at pH2.0, it decreases from pH4.0 to pH12.0 and has retained ~ 40% activity in these pHs. Both circular dichroism and intrinsic Trp fluorescence studies revealed conformational stability of protein structure in wide range of temperature and pH. Enzyme activity enhances in presence of non-ionic surfactants like Tween 20 and TritonX-100. Further, inhibitors of the active site residues including PMSF and DEPC alone were unable to inhibit enzyme activity, while cumulative presence of calcium and inhibitors reduces enzyme activity to 90% indicating conformational changes in the protein. Molecular simulation dynamics analysis revealed a calcium binding site near the lid helix (Asn75-Ile80). Title: Molecular dynamics assisted mechanistic insight of Val430-Ala mutation of Rv1592c protein in isoniazid resistant Mycobacterium tuberculosis Kumar A, Anand PK, Chandel S, Shrivatava A, Kaur J Ref: Curr Comput Aided Drug Des, :, 2020 : PubMed ESTHER: Kumar_2020_Curr.Comput.Aided.Drug.Des__ PubMedSearch: Kumar 2020 Curr.Comput.Aided.Drug.Des PubMedID: 31939732 Gene_locus related to this paper: myctu-MT1628 Abstract BACKGROUND: Multi drug-resistant tuberculosis is a major health threat to humans. Whole genome sequencing of several isoniazid (INH) resistant strains of M. tuberculosis revealed mutations in several genes. Rv1592c was demonstrated as lipolytic enzyme and its expression was up-regulated during isoniazid (INH) treatment. The valine at position 430 of Rv1592c was mutated to alanine frequently in the INH resistant strain of M. tuberculosis. METHODS: In this report, an array of computational approaches was used to understand the role of Val430-Ala mutation in Rv1592c in INH resistance. The impact of mutations on structural stability and degree of INH modification was demonstrated using the molecular dynamics method. The mutation in the Rv1592c gene at V430 position was created by the PCR primer walking method. Mutant and wild type gene was cloned into E. coli-mycobacteria shuttle vector (pVV-16) and expressed in Mycobacterium smegmatis system. The isoniazid susceptibility assay was performed by agar plate culture spot and CFUs count assay. RESULTS: This study demonstrated that the Val430 in Rv1592c makes the part of flap covering the substrate binding cavity. Mutation at Val430-Ala in Rv1592c caused the displacement of the flap region, resulting in uncovering a cavity, which allows accessibility of substrate to the active site cleft. The Val430-Ala mutation in Rv1592c created its structure energetically more stable. RMSD, RMSF and Rg simulation of mutant maintained overall stability throughout the simulation period while the native protein displayed comparatively more fluctuations. Moreover, docking studies showed that INH was bound into the active pocket of the mutant with considerable binding energy (-6.3 kcal/mol). In order to observe constant binding for INH, complexes were simulated for 50 ns. It was observed that after simulation, INH remained bound in the pocket with an increased molecular bonding network with the neighbor amino acid residues. In vitro studies clearly suggested that M. smegmatis expressing mutant has a better survival rate in isoniazid treatment as compared to wild type. CONCLUSION: Overall, this study at the outset suggested that the mutation observed in drug resistant strain provides stability to the Rv1592c protein and increased affinity towards the INH due to flap displacement, leading to the possibility for its modification. In vitro results supported our in silico findings. Title: A Broad Temperature Active Lipase Purified From a Psychrotrophic Bacterium of Sikkim Himalaya With Potential Application in Detergent Formulation Kumar A, Mukhia S, Kumar N, Acharya V, Kumar S, Kumar R Ref: Front Bioeng Biotechnol, 8:642, 2020 : PubMed ESTHER: Kumar_2020_Front.Bioeng.Biotechnol_8_642 PubMedSearch: Kumar 2020 Front.Bioeng.Biotechnol 8 642 PubMedID: 32671041 Abstract Bacterial lipases with activity spanning over a broad temperature and substrate range have several industrial applications. An efficient enzyme-producing bacterium Chryseobacterium polytrichastri ERMR1:04, previously reported from Sikkim Himalaya, was explored for purification and characterization of cold-adapted lipase. Optimum lipase production was observed in 1% (v/v) rice bran oil, pH 7 at 20degC. Size exclusion and hydrophobic interaction chromatography purified the enzyme up to 21.3-fold predicting it to be a hexameric protein of 250 kDa, with 39.8 kDa monomeric unit. MALDI-TOF-MS analysis of the purified lipase showed maximum similarity with alpha/beta hydrolase (lipase superfamily). Biochemical characterization of the purified enzyme revealed optimum pH (8.0), temperature (37degC) and activity over a temperature range of 5-65degC. The tested metals (except Cu(2+) and Fe(2+)) enhanced the enzyme activity and it was tolerant to 5% (v/v) methanol and isopropanol. The Km and Vmax values were determined as 0.104 mM and 3.58 U/mg, respectively for p-nitrophenyl palmitate. Bioinformatics analysis also supported in vitro findings by predicting enzyme's broad temperature and substrate specificity. The compatibility of the purified lipase with regular commercial detergents, coupled with its versatile temperature and substrate range, renders the given enzyme a promising biocatalyst for potential detergent formulations. Title: Aspergillus nidulans: A Potential Resource of the Production of the Native and Heterologous Enzymes for Industrial Applications Kumar A Ref: Int J Microbiol, 2020:8894215, 2020 : PubMed ESTHER: Kumar_2020_Int.J.Microbiol_2020_8894215 PubMedSearch: Kumar 2020 Int.J.Microbiol 2020 8894215 PubMedID: 32802076 Abstract Aspergillus nidulans is a filamentous fungus that is a potential resource for industrial enzymes. It is a versatile fungal cell factory that can synthesize various industrial enzymes such as cellulases, beta-glucosidases, hemicellulases, laccases, lipases, proteases, beta-galactosidases, tannases, keratinase, cutinases, and aryl alcohol oxidase. A. nidulans has shown the potential to utilize low-cost substrates such as wheat bran, rice straw, sugarcane bagasse, rice bran, coir pith, black gram residue, and chicken feathers to produce enzymes cost-effectively. A. nidulans has also been known as a model organism for the production of heterologous enzymes. Several studies reported genetically engineered strains of A. nidulans for the production of different enzymes. Native as well as heterologous enzymes of A. nidulans have been employed for various industrial processes. Title: Candida antarctica lipase-B-catalyzed kinetic resolution of 1,3-dialkyl-3-hydroxymethyl oxindoles Kumar N, Kumar A, Sahoo SC, Chimni SS Ref: Chirality, 32:1377, 2020 : PubMed ESTHER: Kumar_2020_Chirality_32_1377 PubMedSearch: Kumar 2020 Chirality 32 1377 PubMedID: 33141985 Abstract Candida antarctica (CAL-B) lipase-catalyzed resolution of 1,3-dialkyl-3-hydroxymethyl oxindoles has been performed to obtain (R)-1,3-dialkyl-3-acetoxymethyl oxindoles with up to 99% ee and (S)-1,3-dialkyl-3-hydroxymethyl oxindoles with up to 78% ee using vinyl acetate as acylating agent and acetonitrile as solvent transforming (S)-3-allyl-3-hydroxymethyl oxindole to (3S)-1'-benzyl-5-(iodomethyl)-4,5-dihydro-2H-spiro[furan-3,3'-indolin]-2'-one. The optically active 3-substituted-3-hydroxymethyl oxindoles and spiro-oxindoles are among the key synthons in the synthesis of potentially biologically active molecules. Title: Anti-Acetylcholinesterase Activities of Mono-Herbal Extracts and Exhibited Synergistic Effects of the Phytoconstituents: A Biochemical and Computational Study Balkrishna A, Pokhrel S, Tomer M, Verma S, Kumar A, Nain P, Gupta A, Varshney A Ref: Molecules, 24:, 2019 : PubMed ESTHER: Balkrishna_2019_Molecules_24_ PubMedSearch: Balkrishna 2019 Molecules 24 PubMedID: 31752124 Inhibitor(s) related to this paper: Palmatine Abstract Alzheimer's disease (AD), a neurodegenerative disease, is the most common form of dementia. Inhibition of acetylcholinesterase (AChE) is a common strategy for the treatment of AD. In this study, aqueous, hydro-methanolic, and methanolic extracts of five potent herbal extracts were tested for their in vitro anti-AChE activity. Among all, the Tinospora cordifolia (Giloy) methanolic fraction performed better with an IC50 of 202.64 microg/mL. Of the HPLC analyzed components of T. cordifolia (methanolic extract), palmatine and berberine performed better (IC50 0.66 and 0.94 microg/mL, respectively) as compared to gallic acid and the tool compound "galantamine hydrobromide" (IC50 7.89 and 1.45 microg/mL, respectively). Mode of inhibition of palmatine and berberine was non-competitive, while the mode was competitive for the tool compound. Combinations of individual alkaloids palmatine and berberine resulted in a synergistic effect for AChE inhibition. Therefore, the AChE inhibition by the methanolic extract of T. cordifolia was probably due to the synergism of the isoquinoline alkaloids. Upon molecular docking, it was observed that palmatine and berberine preferred the peripheral anionic site (PAS) of AChE, with pi-interactions to PAS residue Trp286, indicating that it may hinder the substrate binding by partially blocking the entrance of the gorge of the active site or the product release. Title: Protein-Protein Interactions and Aggregation Inhibitors in Alzheimer's Disease Ganeshpurkar A, Swetha R, Kumar D, Gangaram GP, Singh R, Gutti G, Jana S, Kumar A, Singh SK Ref: Curr Top Med Chem, 19:501, 2019 : PubMed ESTHER: Ganeshpurkar_2019_Curr.Top.Med.Chem_19_501 PubMedSearch: Ganeshpurkar 2019 Curr.Top.Med.Chem 19 501 PubMedID: 30836921 Abstract BACKGROUND: Alzheimer's Disease (AD), a multifaceted disorder, involves complex pathophysiology and plethora of protein-protein interactions. Thus such interactions can be exploited to develop anti-AD drugs. OBJECTIVE: The interaction of dynamin-related protein 1, cellular prion protein, phosphoprotein phosphatase 2A and Mint 2 with amyloid beta, etc., studied recently, may have critical role in progression of the disease. Our objective has been to review such studies and their implications in design and development of drugs against the Alzheimer's disease. METHODS: Such studies have been reviewed and critically assessed. RESULTS: Review has led to show how such studies are useful to develop anti-AD drugs. CONCLUSION: There are several PPIs which are current topics of research including Drp1, Abeta interactions with various targets including PrPC, Fyn kinase, NMDAR and mGluR5 and interaction of Mint2 with PDZ domain, etc., and thus have potential role in neurodegeneration and AD. Finally, the multi-targeted approach in AD may be fruitful and opens a new vista for identification and targeting of PPIs in various cellular pathways to find a cure for the disease. Title: Development of pyrazole and spiropyrazoline analogs as multifunctional agents for treatment of Alzheimer's disease Gutti G, Kumar D, Paliwal P, Ganeshpurkar A, Lahre K, Kumar A, Krishnamurthy S, Singh SK Ref: Bioorg Chem, 90:103080, 2019 : PubMed ESTHER: Gutti_2019_Bioorg.Chem_90_103080 PubMedSearch: Gutti 2019 Bioorg.Chem 90 103080 PubMedID: 31271946 Abstract Cholinergic hypothesis of Alzheimer's disease has been advocated as an essential tool in the last couple of decades for the drug development. Here in, we report de novo fragment growing strategy for the design of novel 3,5-diarylpyrazoles and hit optimization of spiropyrazoline derivatives as acetyl cholinesterase inhibitors. Both type of scaffolds numbering forty compounds were synthesized and evaluated for their potencies against AChE, BuChE and PAMPA. Introduction of lipophilic cyclohexane ring in 3,5-diarylpyrazole analogs led to spiropyrazoline derivatives, which facilitated and improved the potencies. Compound 44 (AChE=1.937+/-0.066microM; BuChE=1.166+/-0.088microM; hAChE=1.758+/-0.095microM; Pe=9.491+/-0.34x10(-6)cms(1)) showed positive results, which on further optimization led to the development of compound 67 (AChE=0.464+/-0.166microM; BuChE=0.754+/-0.121microM; hAChE=0.472+/-0.042microM; Pe=13.92+/-0.022x10(-6)cms(1)). Compounds 44 and 67 produced significant displacement of propidium iodide from the peripheral anionic site (PAS) of AChE. They were found to be safer to MC65 cells and decreased metal induced Abeta1-42 aggregation. Further, in-vivo behavioral studies, on scopolamine induced amnesia model, the compounds resulted in better percentage spontaneous alternation scores and were safe, had no influence on locomotion in tested animal groups at dose of 3mg/kg. Early pharmacokinetic assessment of optimized hit molecules was supportive for further drug development. Title: Discovery of novel series of 2-substituted benzo[d]oxazol-5-amine derivatives as multi-target directed ligands for the treatment of Alzheimer's disease Gutti G, Kakarla R, Kumar D, Beohar M, Ganeshpurkar A, Kumar A, Krishnamurthy S, Singh SK Ref: Eur Journal of Medicinal Chemistry, 182:111613, 2019 : PubMed ESTHER: Gutti_2019_Eur.J.Med.Chem_182_111613 PubMedSearch: Gutti 2019 Eur.J.Med.Chem 182 111613 PubMedID: 31437780 Abstract Alzheimer's disease (AD) is associated with multifactorial neuropathological conditions, which include cholinergic deficit, amyloid-beta plaques formation, loss of neuronal plasticity and neuronal death. Treating such multifactorial conditions with a single target directed approach is considered to be inadequate. Accordingly, multi-target directed ligand (MTDL) strategy has been evolved as an auspicious approach for the treatment of AD. In light of that, a library of 2-substituted benzo[d]oxazol-5-amine derivatives (29-39; 86-107) was designed using the scaffold hopping guided MTDLs strategy, synthesized and evaluated through various in-vitro and in-vivo biological studies. The optimal compound 92 exhibited potent inhibitory activities against AChE (IC50 = 0.052+/-0.010muM), BuChE (IC50 = 1.085+/-0.035muM), and significant amyloid-beta aggregation (20muM) inhibition. The compound possessed better blood-brain barrier permeability (Pe=10.80+/-0.055x10(-6)cms(-1)) in PAMPA assay and neuro protective properties (40muM) on SH-SY5Y neuroblastoma cell lines. Furthermore, in-vivo behavioural studies were performed on Y-maze test (scopolamine-induced amnesia model) and Morris water maze test (Abeta1-42 induced ICV rat model). The compound 92, at a dose of 10mg/kg oral administration, demonstrated a substantial improvement of the cognitive and special memory impairment. In summary, both in-vitro and in-vivo investigations evidenced that compound 92 was a potential lead for the discovery of safe and effective disease-modifying agents for AD. Title: Computational and In-Vitro Validation of Natural Molecules as Potential Acetylcholinesterase Inhibitors and Neuroprotective Agents Kumar A, Mehta V, Raj U, Varadwaj PK, Udayabanu M, Yennamalli RM, Singh TR Ref: Curr Alzheimer Res, 16:116, 2019 : PubMed ESTHER: Kumar_2019_Curr.Alzheimer.Res_16_116 PubMedSearch: Kumar 2019 Curr.Alzheimer.Res 16 116 PubMedID: 30543170 Abstract BACKGROUND: Cholinesterase inhibitors are the first line of therapy for the management of Alzheimer's disease (AD), however, it is now established that they provide only temporary and symptomatic relief, besides, having several inherited side-effects. Therefore, an alternative drug discovery method is used to identify new and safer 'disease-modifying drugs'. METHODS: Herein, we screened 646 small molecules of natural origin having reported pharmacological and functional values through in-silico docking studies to predict safer neuromodulatory molecules with potential to modulate acetylcholine metabolism. Further, the potential of the predicted molecules to inhibit acetylcholinesterase (AChE) activity and their ability to protect neurons from degeneration was determined through in-vitro assays. RESULTS: Based on in-silico AChE interaction studies, we predicted quercetin, caffeine, ascorbic acid and gallic acid to be potential AChE inhibitors. We confirmed the AChE inhibitory potential of these molecules through in-vitro AChE inhibition assay and compared results with donepezil and begacestat. Herbal molecules significantly inhibited enzyme activity and inhibition for quercetin and caffeine did not show any significant difference from donepezil. Further, the tested molecules did not show any neurotoxicity against primary (E18) hippocampal neurons. We observed that quercetin and caffeine significantly improved neuronal survival and efficiently protected hippocampal neurons from HgCl2 induced neurodegeneration, which other molecules, including donepezil and begacestat, failed to do. CONCLUSION: Quercetin and caffeine have the potential as "disease-modifying drugs" and may find application in the management of neurological disorders such as AD. Title: Anti-cholinesterase hybrids as multi-target-directed ligands against Alzheimer's disease (1998-2018) Mishra P, Kumar A, Panda G Ref: Bioorganic & Medicinal Chemistry, 27:895, 2019 : PubMed ESTHER: Mishra_2019_Bioorg.Med.Chem_27_895 PubMedSearch: Mishra 2019 Bioorg.Med.Chem 27 895 PubMedID: 30744931 Abstract Alzheimer's disease (AD) is a genetically complex, progressive and irreversible neurodegenerative disorder of the brain which involves multiple associated etiological targets. The complex pathogenesis of AD gave rise to multi-target-directed ligands (MTDLs) principle to combat this dreaded disease. Within this approach, the design and synthesis of hybrids prevailed greatly because of their capability to simultaneously target the intertwined pathogenesis components of the disease. The hybrids include pharmacophoric hybridization of two or more established chemical scaffolds endowed with the desired pharmacological properties into a single moiety. In AD, the primary foundation of medication therapy and drug design strategies includes the inhibition of cholinesterase (ChE) enzymes. Hence the development of ChE inhibition based hybrids is the central choice of AD medicinal chemistry research. To illustrate the progress of ChE inhibition based hybrids and novel targets, we reviewed the medicinal chemistry and pharmacological properties of the multi-target molecules published since 1998-December 2018. We hope that this article will allow the readers to easily follow the evolution of this prominent medicinal chemistry approach to develop a more efficient inhibitor. Title: Synthesis and biological evaluation of indoloquinoline alkaloid cryptolepine and its bromo-derivative as dual cholinesterase inhibitors Nuthakki VK, Mudududdla R, Sharma A, Kumar A, Bharate SB Ref: Bioorg Chem, 90:103062, 2019 : PubMed ESTHER: Nuthakki_2019_Bioorg.Chem_90_103062 PubMedSearch: Nuthakki 2019 Bioorg.Chem 90 103062 PubMedID: 31220673 Abstract Alkaloids have always been a great source of cholinesterase inhibitors. Numerous studies have shown that inhibiting acetylcholinesterase as well as butyrylcholinetserase is advantageous, and have better chances of success in preclinical/ clinical settings. With the objective to discover dual cholinesterase inhibitors, herein we report synthesis and biological evaluation of indoloquinoline alkaloid cryptolepine (1) and its bromo-derivative 2. Our study has shown that cryptolepine (1) and its 2-bromo-derivative 2 are dual inhibitors of acetylcholinesterase and butyrylcholinesterase, the enzymes which are involved in blocking the process of neurotransmission. Cryptolepine inhibits Electrophorus electricus acetylcholinesterase, recombinant human acetylcholinesterase and equine serum butyrylcholinesterase with IC50 values of 267, 485 and 699nM, respectively. The 2-bromo-derivative of cryptolepine also showed inhibition of these enzymes, with IC50 values of 415, 868 and 770nM, respectively. The kinetic studies revealed that cryptolepine inhibits human acetylcholinesterase in a non-competitive manner, with ki value of 0.88microM. Additionally, these alkaloids were also tested against two other important pathological events of Alzheimer's disease viz. stopping the formation of toxic amyloid-beta oligomers (via inhibition of BACE-1), and increasing the amyloid-beta clearance (via P-gp induction). Cryptolepine displayed potent P-gp induction activity at 100nM, in P-gp overexpressing adenocarcinoma LS-180 cells and excellent toxicity window in LS-180 as well as in human neuroblastoma SH-SY5Y cell line. The molecular modeling studies with AChE and BChE have shown that both alkaloids were tightly packed inside the active site gorge (site 1) via multiple pi-pi and cation-pi interactions. Both inhibitors have shown interaction with the allosteric "peripheral anionic site" via hydrophobic interactions. The ADME properties including the BBB permeability were computed for these alkaloids, and were found within the acceptable range. Title: Identification of embelin, a 3-undecyl-1,4-benzoquinone from Embelia ribes as a multitargeted anti-Alzheimer agent Nuthakki VK, Sharma A, Kumar A, Bharate SB Ref: Drug Dev Res, 80:655, 2019 : PubMed ESTHER: Nuthakki_2019_Drug.Dev.Res_80_655 PubMedSearch: Nuthakki 2019 Drug.Dev.Res 80 655 PubMedID: 31050027 Abstract Beta-secreatse (BACE-1) and cholinesterases are clinically validated targets of Alzheimer's disease (AD), for which natural products have provided immense contribution. The multifaceted nature of AD signifies the need of multitargeted agents to tackle this disease. In the search of new natural products as dual BACE-1/cholinesterase inhibitors, a library of pure natural products was screened for inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and BACE-1. The screening efforts have identified 1,4-benzoquinone "embelin," a natural product derived from Embelia ribes displaying inhibition of all three enzymes, with IC50 values of 2.5, 5.4, and 2.1 muM, respectively. This screen has also identified isoquinoline alkaloids papaverine and L-tetrahydropalmatine as AChE inhibitors. Kinetic study has shown that embelin inhibits EeAChE and EqBChE with ki values of 4.59 and 0.57 muM, in an uncompetitive and noncompetitive manner, respectively. The interactions of embelin with allosteric peripheral anionic site of cholinesterases, has further supported the results of kinetic study. Embelin has also enhanced the activity of P-gp in LS-180 cells, the efflux pump which is involved in the clearance of amyloid-beta from AD brain. Further, the cell viability study in neuronal cell line has indicated the excellent therapeutic window of embelin. These results are indicative of the fact that embelin is a multitargeted agent playing role in stopping the formation of amyloid-beta oligomers (via inhibition of BACE-1), improves cholinergic-transmission (via inhibition of AChE/BChE) and increases amyloid-beta clearance (via P-gp induction). Title: Visual hallucinations in Alzheimer's disease do not seem to be associated with chronic hypoperfusion of to visual processing areas V2 and V3 but may be associated with reduced cholinergic input to these areas Sinclair LI, Kumar A, Darreh-Shori T, Love S Ref: Alzheimers Res Ther, 11:80, 2019 : PubMed ESTHER: Sinclair_2019_Alzheimers.Res.Ther_11_80 PubMedSearch: Sinclair 2019 Alzheimers.Res.Ther 11 80 PubMedID: 31511061 Abstract BACKGROUND: Up to 20% of patients with AD experience hallucinations. The pathological substrate is not known. Visual hallucinations (VH) are more common in dementia with Lewy bodies (DLB). In autopsy studies, up to 60% of patients with AD have concomitant Lewy body pathology. Decreased perfusion of the occipital lobe has been implicated in DLB patients with VH, and post-mortem studies point to both decreased cholinergic activity and reduced oxygenation of the occipital cortex in DLB. METHODS: We used biochemical methods to assess microvessel density (level of von Willebrand factor, a marker of endothelial cell content), ante-mortem oxygenation (vascular endothelial growth factor, a marker of tissue hypoxia; myelin-associated glycoprotein to proteolipid protein-1 ratio, a measure of tissue oxygenation relative to metabolic demand), cholinergic innervation (acetylcholinesterase and choline acetyltransferase), butyrylcholinesterase and insoluble alpha-synuclein content in the BA18 and BA19 occipital cortex obtained post-mortem from 23 AD patients who had experienced visual hallucinations, 19 AD patients without hallucinations, 19 DLB patients, and 36 controls. The cohorts were matched for age, gender and post-mortem interval. RESULTS: There was no evidence of reduced microvessel density, hypoperfusion or reduction in ChAT activity in AD with visual hallucinations. Acetylcholinesterase activity was reduced in both BA18 and BA19, in all 3 dementia groups, and the concentration was also reduced in BA19 in the DLB and AD without visual hallucinations groups. Insoluble alpha-synuclein was raised in the DLB group in both areas but not in AD either with or without visual hallucinations. CONCLUSIONS: Our results suggest that visual hallucinations in AD are associated with cholinergic denervation rather than chronic hypoperfusion or alpha-synuclein accumulation in visual processing areas of the occipital cortex. Title: Targeting oxidative stress, acetylcholinesterase, proinflammatory cytokine, dopamine and GABA by eucalyptus oil (Eucalyptus globulus) to alleviate ketamine-induced psychosis in rats Yadav M, Jindal DK, Parle M, Kumar A, Dhingra S Ref: Inflammopharmacology, 27:301, 2019 : PubMed ESTHER: Yadav_2019_Inflammopharmacology_27_301 PubMedSearch: Yadav 2019 Inflammopharmacology 27 301 PubMedID: 29464495 Abstract Essential oil of eucalyptus species is among the most common traded essential oils in the world. There is an increasing interest in the application of eucalyptus oil as a natural additive in food and pharmaceutical industry. The present study was undertaken to identify the phytoconstituents present in the essential oil of Eucalyptus globulus leaves (EO) and ascertain their protective effect against ketamine-induced psychosis in rats. GC-MS technique was used for analysis of phytoconstituents present in EO. Ketamine (50 mg/kg, i.p.) was used to induce psychosis in rats. Photoactometer, forced swim test and pole climb avoidance test were used to evaluate the protective effects of the EO (500, 1000 and 2000 mg/kg, p.o.) on acute and chronic administration. Bar test was used to test the side effect of EO. Biochemical and neurochemical estimations were carried out to explore the possible mechanism of action. GC-MS analysis of EO showed the presence of a number of biologically active compounds. EO at the dose of 500, 1000 and 2000 mg/kg, p.o. on acute and chronic administration, decreased locomotor activity, immobility duration and latency to climb the pole. EO was effective to facilitate the release of GABA, increase GSH levels, inhibit dopamine neurotransmission and decrease TNF-alpha levels as well as diminish AChE activity in different regions of the brain. EO at the dose of 500, 1000 mg/kg did not produce cataleptic behavior in rats. EO at the dose of 500, 1000 mg/kg produced protective effects against ketamine-induced psychosis and can be further explored clinically against neuropsychiatric disorders. Title: Carboxypeptidase in prolyl oligopeptidase family: Unique enzyme activation and substrate-screening mechanisms Yadav P, Goyal VD, Gaur NK, Kumar A, Gokhale SM, Jamdar SN, Makde RD Ref: Journal of Biological Chemistry, 294:89, 2019 : PubMed ESTHER: Yadav_2019_J.Biol.Chem_294_89 PubMedSearch: Yadav 2019 J.Biol.Chem 294 89 PubMedID: 30409909 Gene_locus related to this paper: deira-DR0165 Abstract Serine peptidases of the prolyl oligopeptidase (POP) family are of substantial therapeutic importance because of their involvement in diseases such as diabetes, cancer, neurological diseases, and autoimmune disorders. Proper annotation and knowledge of substrate specificity mechanisms in this family are highly valuable. Although endopeptidase, dipeptidyl peptidase, tripeptidyl peptidase, and acylaminoacyl peptidase activities have been reported previously, here we report the first instance of carboxypeptidase activity in a POP family member. We determined the crystal structures of this carboxypeptidase, an S9C subfamily member from Deinococcus radiodurans, in its active and inactive states at 2.3-A resolution, providing an unprecedented view of assembly and disassembly of the active site mediated by an arginine residue. We observed that this residue is poised to bind substrate in the active structure and disrupts the catalytic triad in the inactive structure. The assembly of the active site is accompanied by the ordering of gating loops, which reduces the effective size of the oligomeric pore. This prevents the entry of larger peptides and constitutes a novel mechanism for substrate screening. Furthermore, we observed structural adaptations that enable its carboxypeptidase activity, with a unique loop and two arginine residues in the active site cavity orienting the peptide substrate for catalysis. Using these structural features, we identified homologs of this enzyme in the POP family and confirmed the presence of carboxypeptidase activity in one of them. In conclusion, we have identified a new type within POP enzymes that exhibits not only unique activity but also a novel substrate-screening mechanism. Title: Tramadol ameliorates behavioural, biochemical, mitochondrial and histological alterations in ICV-STZ-induced sporadic dementia of Alzheimer's type in rats Dhull DK, Kumar A Ref: Inflammopharmacology, 26:925, 2018 : PubMed ESTHER: Dhull_2018_Inflammopharmacology_26_925 PubMedSearch: Dhull 2018 Inflammopharmacology 26 925 PubMedID: 29249049 Abstract Alzheimer disease represents a major public health issue with limited therapeutic interventions. We explored the possibility of therapeutic approach by repurposing of tramadol in a sporadic animal model of Alzheimer's type. Streptozocin (STZ 3 mg/kg; bilaterally) was injected to male SD rats through intracerebroventricular (ICV) route. Drug treatment was started just after streptozocin administration and continued for 3 weeks. The rats were killed on the 21st day following the last behavioral test, and cytoplasmic fractions of the hippocampus and pre-frontal cortex were prepared for the quantification of acetylcholinesterase, oxidative stress parameter, mitochondrial enzymes activity and histological examination. Tramadol (5, 10 and 20 mg/kg, i.p.) was used as a treatment drug, and memantine (10 mg/kg, i.p.) was used as a standard. Tramadol significantly attenuated behavioral, biochemical, mitochondrial and histological alterations at low (5 mg/kg) and intermediate (10 mg/kg) dose, suggesting its neuroprotective potential in ICV-STZ-treated rats. Further, the neuroprotective effect of tramadol (10 mg/kg) was comparable to memantine (10 mg/kg). In conclusion, our results indicate the effectiveness of tramadol in preventing ICV-STZ-induced cognitive impairment as well as mito-oxidative stress. Further, these findings reveal the possibility of MOR agonist as a therapeutic approach for sporadic Alzheimer disease. Title: Synthesis, molecular docking and cholinesterase inhibitory activity of hydroxylated 2-phenylbenzofuran derivatives Fais A, Kumar A, Medda R, Pintus F, Delogu F, Matos MJ, Era B, Delogu GL Ref: Bioorg Chem, 84:302, 2018 : PubMed ESTHER: Fais_2018_Bioorg.Chem_84_302 PubMedSearch: Fais 2018 Bioorg.Chem 84 302 PubMedID: 30529848 Abstract We have designed, synthesized and evaluated a series of hydroxylated 2-phenylbenzofuran derivatives as potential cholinesterase inhibitors. Starting from a series of 2-phenylbenzofurans previously published, in this paper we present a complete synthesis and the influence on the activity of one or two hydroxyl groups located in meta or in meta and para positions respectively of the 2-phenyl ring and highlight the importance of position of hydroxyl groups. Moreover, simultaneous introduction of halogen at position 7 of the benzofuran scaffold resulted in an improved inhibitory activity against the enzyme. To further provide molecular insight and to identify the most probable ligand-binding site of the protein, docking studies were performed for the top-ranked compounds. Docking results revealed conserved ligand-binding residues and supported the role of catalytic site residues in enzyme inhibition. Title: Novel 2-pheynlbenzofuran derivatives as selective butyrylcholinesterase inhibitors for Alzheimer's disease Kumar A, Pintus F, Di Petrillo A, Medda R, Caria P, Matos MJ, Vina D, Pieroni E, Delogu F and Fais A <2 more author(s)> Kumar A, Pintus F, Di Petrillo A, Medda R, Caria P, Matos MJ, Vina D, Pieroni E, Delogu F, Era B, Delogu GL, Fais A (- 2) Ref: Sci Rep, 8:4424, 2018 : PubMed ESTHER: Kumar_2018_Sci.Rep_8_4424 PubMedSearch: Kumar 2018 Sci.Rep 8 4424 PubMedID: 29535344 Abstract Alzheimer's disease (AD) is a neurodegenerative disorder representing the leading cause of dementia and is affecting nearly 44 million people worldwide. AD is characterized by a progressive decline in acetylcholine levels in the cholinergic systems, which results in severe memory loss and cognitive impairments. Expression levels and activity of butyrylcholinesterase (BChE) enzyme has been noted to increase significantly in the late stages of AD, thus making it a viable drug target. A series of hydroxylated 2-phenylbenzofurans compounds were designed, synthesized and their inhibitory activities toward acetylcholinesterase (AChE) and BChE enzymes were evaluated. Two compounds (15 and 17) displayed higher inhibitory activity towards BChE with IC50 values of 6.23 muM and 3.57 muM, and a good antioxidant activity with EC50 values 14.9 muM and 16.7 muM, respectively. The same compounds further exhibited selective inhibitory activity against BChE over AChE. Computational studies were used to compare protein-binding pockets and evaluate the interaction fingerprints of the compound. Molecular simulations showed a conserved protein residue interaction network between the compounds, resulting in similar interaction energy values. Thus, combination of biochemical and computational approaches could represent rational guidelines for further structural modification of these hydroxy-benzofuran derivatives as future drugs for treatment of AD. Title: Use of Simplified Molecular Input Line Entry System and molecular graph based descriptors in prediction and design of pancreatic lipase inhibitors Kumar A, Chauhan S Ref: Future Med Chem, 10:1603, 2018 : PubMed ESTHER: Kumar_2018_Future.Med.Chem_10_1603 PubMedSearch: Kumar 2018 Future.Med.Chem 10 1603 PubMedID: 30028205 Abstract AIM: The inhibition of pancreatic lipase (PL) enzyme is the most explored strategy for the treatment of obesity. The present study describes the development of quantitative structure-activity relationship (QSAR) models for a diverse set of 293 PL inhibitors by means of the Monte Carlo optimization technique. Methodology & results: The hybrid optimal descriptors were used to build QSAR models with three subsets of three splits. The developed QSAR models were further validated with corresponding external sets. The best QSAR model has the following statistical particulars: R(2) = 0.752, Q LOO 2 = 0 . 736 for the test set and R(2) = 0.768, Q F 1 2 = 0 . 628 , Q F 2 2 = 0 . 621 for the validation set. CONCLUSION: The developed QSAR models were robust, stable and predictive and led to the design of novel PL inhibitors. Title: Soluble Abeta42 Acts as Allosteric Activator of the Core Cholinergic Enzyme Choline Acetyltransferase Kumar A, Lana E, Kumar R, Lithner CU, Darreh-Shori T Ref: Front Mol Neurosci, 11:327, 2018 : PubMed ESTHER: Kumar_2018_Front.Mol.Neurosci_11_327 PubMedSearch: Kumar 2018 Front.Mol.Neurosci 11 327 PubMedID: 30271321 Abstract Two major questions in the field of Alzheimer-type dementia remain elusive. One is the native function of amyloid-beta (Abeta) peptides and the other is an early deficit in the central cholinergic network. Nevertheless, recent evidence suggests that Abeta peptides are involved in the regulation of acetylcholine (ACh) homeostasis either by allosteric activation of ACh-degrading cholinesterases or by inhibiting the high-affinity choline uptake transporter. In the current study, we report that Abeta peptides, in particular Abeta42, allosterically enhances the catalytic rate of the core-cholinergic enzyme choline acetyltransferase (ChAT), responsible for biosynthesis of ACh. Detailed in vitro enzyme kinetic analysis indicated that both soluble Abeta40 and Abeta42 enhanced the catalytic efficiency of ChAT by approximately 21% and 26% at physiological concentration ranges found in human cerebrospinal fluid (CSF). Further analyses indicated that activation of ChAT by Abeta was highly specific. Intriguingly, Abeta42 exhibited an EC50 of activation potency at 10-fold lower concentrations compared to Abeta40. The activation was persistent even in the presence of a physiological Abeta 40/42 mixture ratio, expected in human CSF. In conclusion, we report for the first time that Abeta42 peptide acts as allosteric enhancers of ACh-biosynthesizing enzyme ChAT. Together with two previous observations, this points to a complex molecular cross-talk between Abeta and the enzymatic machinery involved in maintaining cellular, synaptic and extra-synaptic ACh homeostasis, warranting further investigation. Title: Rv1288, a Two Domain, Cell Wall Anchored, Nutrient Stress Inducible Carboxyl-Esterase of Mycobacterium tuberculosis, Modulates Cell Wall Lipid Maan P, Kumar A, Kaur J Ref: Front Cell Infect Microbiol, 8:421, 2018 : PubMed ESTHER: Maan_2018_Front.Cell.Infect.Microbiol_8_421 PubMedSearch: Maan 2018 Front.Cell.Infect.Microbiol 8 421 PubMedID: 30560095 Gene_locus related to this paper: myctu-yc88 Abstract Rv1288, a conserved hypothetical protein of M. tuberculosis (M.tb), was recently characterized as two-domain esterase enzyme by in silico study. In the present study, Rv1288 and its domains (Est and Lyt) were cloned individually from M.tb into E. coli for expression and purification. The purified rRv1288 and rEst proteins exhibited lipolytic activity with medium chain length esters as optimum substrates, while Lyt domain did not show enzymatic activity. However, presence of Lyt domain resulted in enhanced rate of protein aggregation at higher temperature. Both rRv1288 and rEst followed the similar patterns of substrate specificity, temperature and pH activity. Site directed mutagenesis confirmed the Ser-294, Asp-391 and His-425 as catalytic site residues. Rv1288 was found to be present in cell wall fraction of M.tb H37Ra. Peptidoglycan binding activity of Rv1288 and its domains demonstrated that the Lyt domain is essential for anchoring protein to the cell wall. Expression of rv1288 was up regulated in M.tb under nutrient starved condition. Over expression of rv1288 in surrogate host M. smegmatis led to change in colony morphology, enhanced pellicle and aggregate formation that might be linked with the changed lipid composition of bacterial cell wall. Cell wall of M. smegmatis expressing rv1288 had higher amount of lipids, with a significant increase in trehalose dimycolate content. Rv1288 also leads to increase in drug resistance of M. smegmatis. Rv1288 also enhanced the intracellular survival of M. smegmatis in Raw264.7 cell line. Overall, this study suggested that Rv1288, a cell wall localized carboxyl hydrolase with mycolyl-transferase activity, modulated the cell wall lipids to favor the survival of bacteria under stress condition. Title: Synergistic action of ursolic acid and metformin in experimental model of insulin resistance and related behavioral alterations Mourya A, Akhtar A, Ahuja S, Sah SP, Kumar A Ref: European Journal of Pharmacology, 835:31, 2018 : PubMed ESTHER: Mourya_2018_Eur.J.Pharmacol_835_31 PubMedSearch: Mourya 2018 Eur.J.Pharmacol 835 31 PubMedID: 30075220 Abstract Chronic restraint stress (CRS) is known to cause metabolic and neurological complications in a number of ways. Prolonged exposure to stress evident by increased corticosterone level led to impaired altered insulin signaling and oxidative stress in mice, in the present study. Impaired insulin signaling or insulin resistance was characterized by hyperglycemia, hyperinsulinemia, hyperlipidemia, hypoadiponectinemia, increased glycosylated haemoglobin and HOMA-IR. It was also associated with increased proinflammatory cytokine TNF-alpha levels. CRS also caused significant increase in acetylcholinesterase activity and oxidative stress in brain along with cognitive impairment in behavioral test. Ursolic acid, metformin, gliclazide and their combinations when administered daily for 30 days significantly improved insulin sensitivity apart from behavioral and biochemical alterations in stressed mice. Treatment with drugs also decreased serum corticosterone and TNF-alpha levels. The findings of our study revealed that improvement in insulin sensitivity, learning and cognitive performance in stressed mice was attributed to attenuation of proinflammatory cytokines and oxidative stress. Moreover, combination of [Metformin (150mg/kg) +Ursolic acid (10mg/kg)] produced enhanced improvement in insulin sensitivity and cognitive impairment as compared to their individual effects, suggesting possibly the common mode of anti-inflammatory and antioxidant mechanisms. Title: Neuromodulatory potential of phenylpropanoids; para-methoxycinnamic acid and ethyl-p-methoxycinnamate on aluminum-induced memory deficit in rats Rijal S, Changdar N, Kinra M, Kumar A, Nampoothiri M, Arora D, Shenoy RR, Pai KSR, Joseph A, Mudgal J Ref: Toxicol Mech Methods, :1, 2018 : PubMed ESTHER: Rijal_2018_Toxicol.Mech.Methods__1 PubMedSearch: Rijal 2018 Toxicol.Mech.Methods 1 PubMedID: 30588862 Abstract Para-methoxycinnamic acid (PMCA) and Ethyl-p-methoxycinnamate (EPMC) are reported to possess neuroprotective effect in reversing an acute memory deficit. However, there is a dearth of evidence for their therapeutic effect in chronic memory deficit. Thus, there is a scope to study these derivatives against the chronic model of cognitive dysfunction. The present study was aimed to determine the cognitive enhancing activity of PMCA and EPMC in aluminum-induced chronic dementia. Cognitive enhancing property of PMCA and EPMC was assessed using Morris water maze by analyzing spatial memory parameters such as escape latency, D-quadrant latency, and island entries. To find a possible mechanism, the effect of test compounds on altered acetylcholinesterase activity and oxidative stress was determined in the hippocampus and frontal cortex of rats. Docking interaction of these derivatives with acetylcholinesterase enzyme and glutamate receptors were also studied. Treatment with PMCA and EPMC showed a significant improvement in spatial memory markers and altered hippocampal AChE activity in rats with cognitive dysfunction. The implication of hippocampal and cortical oxidative stress in memory impairment was confirmed with decreased catalase/increased TBARS in rats. PMCA and EPMC reversed the oxidative stress in the brain by negatively affecting TBARS levels. Against depleted catalase levels, PMCA was more effective than EPMC in raising the depleted catalase levels. In silico analysis revealed poor affinity of EPMC and PMCA with AChE enzyme and glutamate receptor. To conclude, PMCA and EPMC exerted cognitive enhancing property independent of direct AChE and glutamate receptor inhibition. Title: Binary combinations of organophosphorus and synthetic pyrethroids are more potent acetylcholinesterase inhibitors than organophosphorus and carbamate mixtures: An in vitro assessment Arora S, Balotra S, Pandey G, Kumar A Ref: Toxicol Lett, 268:8, 2017 : PubMed ESTHER: Arora_2017_Toxicol.Lett_268_8 PubMedSearch: Arora 2017 Toxicol.Lett 268 8 PubMedID: 27988393 Abstract Anticholinesterase insecticides such as organophosphorous (OP) and carbamates pesticides (CB); and synthetic pyrethroids (SP) pesticides commonly co-occur in the environment. This raises the possibility of antagonistic, additive, or synergistic neurotoxicity in exposed organisms. Acetylcholinesterase (AChE) inhibition has been demonstrated to be useful as a biomarker for exposure to OP and CBs in many environments. This study investigated the response of housefly (Musca domestica) head AChE (HF-AChE) exposed to five OPs; chlorpyrifos (CPF), malathion (MLT), triazophos (TRZ), monocrotophos (MCP) and profenofos (PRF) and two CBs; carbaryl (CRB) and carbofuran (CBF) as individual compounds and as binary mixtures of OPs and CBs under in vitro conditions. In addition, the selected OPs and CBs were evaluated for their toxicity in binary combinations with two SPs; deltamethrin (DLT) and cypermethrin (CYP) at fixed concentrations of 0.1 and 10mug/L. The toxicological interaction of five OPs with two CBs pesticides was evaluated under oxidised and un-oxidised conditions using a toxic unit (TU) approach and a concentration addition (CA) model. Pyrethroid combinations were assessed only under oxidised conditions. Since OPs and CBs act by a similar mechanism of inhibition of AChE, a dose additive effect was expected, but not conclusively found. TRZ with either CBF or CRB exhibited synergism under oxidised and un-oxidised conditions but the degree of synergism was stronger under un-oxidised conditions. Additivity was exhibited by CBF+MCP, CRB+MCP, CRB+MLT and CBF+MCP under un-oxidised conditions and CRB+MCP and CRB+CPF under oxidised conditions. Pyrethorids in combination with OPs (TRZ, MLT and CPF) were highly synergistic. In the present study, we used pure housefly head AChE without any interference of monooxygenase and/or esterase enzyme activities. Therefore these other enzymes were not producing the observed deviations from concentration-addition in the binary combinations between OPs, CBs and SPs. The mechanisms of OP, CB and SP interactions in pesticide mixtures requires further investigation. Title: Calcineurin inhibitors improve memory loss and neuropathological changes in mouse model of dementia Kumar A, Singh N Ref: Pharmacol Biochem Behav, 153:147, 2017 : PubMed ESTHER: Kumar_2017_Pharmacol.Biochem.Behav_153_147 PubMedSearch: Kumar 2017 Pharmacol.Biochem.Behav 153 147 PubMedID: 28063945 Abstract AIM: The present study was designed to investigate the potential of Cyclosporine (CsA) and Tacrolimus, the inhibitors of calcineurin (CaN) in cognitive deficits of mice. Title: Inhibitor of Phosphodiestearse-4 improves memory deficits, oxidative stress, neuroinflammation and neuropathological alterations in mouse models of dementia of Alzheimer's Type Kumar A, Singh N Ref: Biomed Pharmacother, 88:698, 2017 : PubMed ESTHER: Kumar_2017_Biomed.Pharmacother_88_698 PubMedSearch: Kumar 2017 Biomed.Pharmacother 88 698 PubMedID: 28152479 Abstract The study investigates the potential of Rolipram a phosphodiesterase-4 inhibitor in cognitive deficits induced by streptozotocin (STZ, 3mg/kg intracerebroventricularly) and natural ageing in mice. Morris water maze (MWM) test was employed to evaluate learning and memory of the animals. Extent of oxidative stress was measured by estimating the levels of brain glutathione (GSH) and thiobarbituric acid reactive species (TBARS). Brain acetylcholinestrase (AChE) activity was also estimated. The brain activity of myeloperoxidase (MPO) was measured as a marker of inflammation. STZ and ageing results in marked decline in MWM performance of the animals, reflecting impairment of learning and memory. STZ treated mice and aged mice exhibited a marked accentuation of AChE activity, TBARS and MPO activity along with fall in GSH level. Further the stained micrographs of STZ treated mice and aged mice indicate pathological changes, severe neutrophilic infiltration and amyloid deposition. Rolipram treatment significantly attenuated STZ induced and age related memory deficits, biochemical and histopathological alterations. The findings demonstrate the potential of Rolipram in memory dysfunctions which may probably be attributed to its anti-cholinesterase, anti-amyloid, anti-oxidative and anti-inflammatory effects. The study concludes that PDE-4 can be explored as a potential therapeutic target in dementia. Title: Pharmacological activation of protein kinase A improves memory loss and neuropathological changes in a mouse model of dementia of Alzheimer's type Kumar A, Singh N Ref: Behav Pharmacol, 28:187, 2017 : PubMed ESTHER: Kumar_2017_Behav.Pharmacol_28_187 PubMedSearch: Kumar 2017 Behav.Pharmacol 28 187 PubMedID: 28177982 Abstract The study investigates the therapeutic potential of the protein kinase A (PKA) activator forskolin in cognitive deficits of mice. Streptozotocin (STZ) [3 mg/kg, intracerebroventricularly (i.c.v.)] was used to induce memory deficits in mice, whereas aged mice served as natural model of dementia. Forskolin (2.5, 5, and 10 mg/kg/day, oral) treatment was administered to i.c.v. STZ-treated and aged mice for 14 days. The Morris Water Maze test was used to evaluate learning and memory. Estimation of brain acetylcholinesterase (AChE) activity, brain glutathione, thiobarbituric acid-reactive species, brain myeloperoxidase levels, and histopathological studies were also performed. Both STZ i.c.v. and aging resulted in a marked decline in Morris Water Maze performance, reflecting impairment of learning and memory. STZ i.c.v.-treated mice and aged mice showed a marked accentuation of AChE activity, thiobarbituric acid-reactive species and myeloperoxidase levels along with a decrease in the glutathione level. Further, the stained micrographs of STZ-treated mice and aged mice indicated pathological changes, severe neutrophilic infiltration, and amyloid deposition. Forskolin treatment significantly attenuated STZ-induced and age-related memory deficits, and biochemical and histopathological alterations. The findings indicate that the PKA activator forskolin probably alleviated memory deficits by virtue of its anticholinesterase, antiamyloid, antioxidative, and anti-inflammatory effects. It is concluded that PKA could be explored as a potential therapeutic target in dementia. Title: Rv0774c, an iron stress inducible, extracellular esterase is involved in immune-suppression associated with altered cytokine and TLR2 expression Kumar A, Singh SM, Singh R, Kaur J Ref: Int J Med Microbiol, 307:126, 2017 : PubMed ESTHER: Kumar_2017_Int.J.Med.Microbiol_307_126 PubMedSearch: Kumar 2017 Int.J.Med.Microbiol 307 126 PubMedID: 28161108 Gene_locus related to this paper: myctu-RV0774C Abstract Tuberculosis, one of the leading cause of death from infectious diseases, is caused by Mycobacterium tuberculosis. The genome of M. tuberculosis has been sequenced and nearly 40% of the whole genome sequence was categorized as hypothetical. Rv0774c was annotated as membrane exported hypothetical protein in TB database. In silico analysis revealed that Rv0774c is a paralog of PE-PGRS multi gene family with 100 aa N-terminal domain similar to PE domain of PE-PGRS proteins. Its C-terminal domain is quite different from PGRS domain, having characteristic lipase signature GXSXG & HG and catalytic residues predicted for lipolytic activity. Therefore, DNA coding for Rv0774c (303 aa), its N-terminal (1-100 aa) and C- terminal domain (100-303 aa) were separately cloned from M. tuberculosis and were over expressed in E. coli. Rv0774c gene and its C-terminal lipolytic domain preferably hydrolyzed short chain esters. Though no enzyme activity was observed in N-terminus PE like domain, it was demonstrated to enhance the thermostability of full length Rv0774c. Tetrahydrolipstatin inhibited the enzyme activity and predicted catalytic residues (Ser-185, Asp-255 and His-281) were confirmed by site directed mutagenesis. Rv0774c was secreted out in culture media by M. tuberculosis and was up-regulated in iron limiting conditions. Treatment of THP-1 cells with rRv0774c resulted in a decline in the LPS induced production of NO and expression of iNOS. rRv0774c treated THP-1 cells also showed an enhanced expression of IL-10 and TLR2. On contrary, it suppressed the LPS induced production of IL-12, chemokines MCP-1 and IL-8. Rv0774c inhibited the LPS induced phosphorylation of p38. These observations suggested that Rv0774c could modulate the pro-inflammatory immune response to support intracellular survival of the mycobacterium. Title: The immunosuppressive effects of a novel recombinant LipQ (Rv2485c) protein of Mycobacterium tuberculosis on human macrophage cell lines Kumar A, Manisha, Sangha GK, Shrivastava A, Kaur J Ref: Microb Pathog, 107:361, 2017 : PubMed ESTHER: Kumar_2017_Microb.Pathog_107_361 PubMedSearch: Kumar 2017 Microb.Pathog 107 361 PubMedID: 28412202 Gene_locus related to this paper: myctu-Rv2485c Abstract Mycobacterium tuberculosis (MTB), an intracellular pathogen, still represents a major global health challenge. A number of mycobacterial macromolecules have been shown to target biological processes within host macrophages; however, the exact mechanism for the majority of these host pathogen interactions is still poorly understood. Moreover, the lipid metabolic pathway is one of the most important physiologic pathways that plays a vital role in the survival and infection of Mycobacterium tuberculosis. In present study, we investigated the effect of rLipQ from Mycobacterium tuberculosis H37Rv on macrophage functions in vitro.Our results demonstrate that rLipQ significantly lowers the expression level of pro-inflammatory cytokines (TNF-alpha& IFN-gamma) and augments the level of anti inflammatory cytokines such as IL-4 & IL-10as compared to LPS stimulated macrophages. An up-regulation of anti-inflammatory and down-regulation of pro-inflammatory cytokines levels in rLipQ pretreated macrophages implies immuno-modulatory functions in TB patients. Interestingly, rLipQ also inhibited the expression of iNOS, TLR-2 and transcription factor NF-kB in LPS stimulated macrophages whereas the expression of TLR-4 remains unchanged. The inhibition in the expression of these signaling molecules has been correlated to the inhibition of NO production in macrophages. Taken together, these studies demonstrate that rLipQ is a novel lipase that is highly immunogenic and may play an important role in the virulence and pathogenesis of M. tuberculosis infection, by altering the balance of cytokines, which might help to assess prognosis and contribute to a better understanding against host-pathogen interactions. Title: Recent advances in the neurobiology and neuropharmacology of Alzheimer's disease Kumar K, Kumar A, Keegan RM, Deshmukh R Ref: Biomed Pharmacother, 98:297, 2017 : PubMed ESTHER: Kumar_2017_Biomed.Pharmacother_98_297 PubMedSearch: Kumar 2017 Biomed.Pharmacother 98 297 PubMedID: 29274586 Abstract Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by progressive deterioration of cognitive functions. The pathological hallmarks are extracellular deposits of amyloid plaques and intracellular neurofibrillary tangles of tau protein. The cognitive deficits seen are thought to be due to synaptic dysfunction and neurochemical deficiencies. Various neurochemical abnormalities have been observed during progressive ageing, and are linked to cognitive abnormalities as seen with the sporadic form of AD. Acetylcholinesterase inhibitors are one of the major therapeutic strategies used for the treatment of AD. During the last decade, various new therapeutic strategies have shown beneficial effects in preclinical studies and under clinical development for the treatment of AD. The present review is aimed at discussing the neurobiology of AD and association of neurochemical abnormalities associated with cognitive deterioration and new therapeutic strategies for the treatment of AD. Title: DMSO: A Mixed-Competitive Inhibitor of Human Acetylcholinesterase Kumar A, Darreh-Shori T Ref: ACS Chem Neurosci, 8:2618, 2017 : PubMed ESTHER: Kumar_2017_ACS.Chem.Neurosci_8_2618 PubMedSearch: Kumar 2017 ACS.Chem.Neurosci 8 2618 PubMedID: 29017007 Inhibitor(s) related to this paper: DMSO Abstract Dimethyl sulfoxide (DMSO) is the most common organic solvent used in biochemical and cellular assays during drug discovery programs. Despite its wide use, the effect of DMSO on several enzyme classes, which are crucial targets of the new therapeutic agents, are still unexplored. Here, we report the detailed biochemical analysis of the effects of DMSO on the human acetylcholine-degrading enzyme, acetylcholinesterase (AChE), the primary target of current Alzheimer's therapeutics. Our analysis showed that DMSO is a considerably potent and highly selective irreversible mixed-competitive inhibitor of human AChE with IC50 values in the lower millimolar range, corresponding to 0.88% to 2.6% DMSO (v/v). Most importantly, 1-4% (v/v) DMSO, the commonly used experimental concentrations, showed approximately 37-80% inhibition of human AChE activity. We believe that our results will assist in developing stringent protocols and help in the better interpretation of experimental outcomes during screening and biological evaluation of new drugs. Title: In-Silico Characterization of a Hypothetical Protein, Rv1288 of Mycobacterium tuberculosis Containing an Esterase Signature and an Uncommon LytE Domain Kumar A, Maan P, Singh G, Kaur J Ref: Curr Comput Aided Drug Des, 13:101, 2017 : PubMed ESTHER: Kumar_2017_Curr.Comput.Aided.Drug.Des_13_101 PubMedSearch: Kumar 2017 Curr.Comput.Aided.Drug.Des 13 101 PubMedID: 27890013 Gene_locus related to this paper: myctu-yc88 Abstract BACKGROUND: Death toll due to tuberculosis is still rising day by day. Whole genome sequence of Mycobacterium tuberculosis has provided a platform to conduct research in order to identify the probable drug target. OBJECTIVES: Out of 4000 gene products of M. tuberculosis, approximately 40% of proteins are annotated as hypothetical. Identifying and characterizing these proteins could provide a new prescriptive for developing new TB drugs. Rv1288, a protein of M. tuberculosis H37Rv has been annotated as a hypothetical protein in database. Attempt has been made to assign a meaningful role to rv1288 gene product in M. tuberculosis life cycle. METHODS: A homology 3D structure of both domains was separately generated and assigned as Rv1288LytE and Rv1288est. Molecular simulation of Rv1288est was carried out for proper structure analysis. To further confirm the predictive role of Rv1288 in mycobacterium life cycle, molecular docking was performed. N-acetyl glucosamine, a major constituent of cell wall was docked with LytE domain, whereas, esterase domain was docked with lipolytic substrate, pNP-ester derivatives and inhibitors THL/PMSF. RESULTS: In-silico analysis revealed that Rv1288 is a two domain protein, an N-terminal LytE domain containing three consecutive LysM motifs and a C-terminal esterase domain of esterase D family. LytE domain has the property to bind N-acetyl glucosamine moieties of peptidoglycan, a major component of cell wall. Detailed in-silico sequence analysis revealed that this LytE domain may help in positioning the esterase domain to the cell wall of mycobacterium. Esterase domain comprised a tetrapeptide motif HGGG, a pentapeptide sequence motif GxSxG and conserved amino acid residues Ser-141, Asp-238 and His-272 which constitute a catalytic triad characteristic of other hormone sensitive lipases/ esterases. Docking studies suggested that THL and PMSF could be the potent inhibitors for Rv1288 protein. CONCLUSION: In the present investigation, we bioinformatically confirmed that Rv1288 is most likely a LytE domain containing lipolytic enzyme showing similarity to hormone sensitive lipases/esterases. Title: Inhibition of Aβ(1-42)Oligomerization, Fibrillization and Acetylcholinesterase Activity by Some Anti-Inflammatory Drugs: An in vitro Study Parmar HS, Assaiya A, Agrawal R, Tiwari S, Mufti I, Jain N, Manivannan E, Banerjee T, Kumar A Ref: Antiinflamm Antiallergy Agents Med Chem, 15:191, 2017 : PubMed ESTHER: Parmar_2017_Antiinflamm.Antiallergy.Agents.Med.Chem_15_191 PubMedSearch: Parmar 2017 Antiinflamm.Antiallergy.Agents.Med.Chem 15 191 PubMedID: 28034279 Abstract BACKGROUND: Number of contradictory reports are available on the effects of antiinflammatory drugs on Alzheimer's disease (AD) including beneficial, adverse and stage dependent effects. We provide insights of the effects exerted by some anti-inflammatory drugs on the chemistry of AD. Title: A Method for Isolation of Extracellular Vesicles and Characterization of Exosomes from Brain Extracellular Space Perez-Gonzalez R, Gauthier SA, Kumar A, Saito M, Levy E Ref: Methods Mol Biol, 1545:139, 2017 : PubMed ESTHER: Perez-Gonzalez_2017_Methods.Mol.Biol_1545_139 PubMedSearch: Perez-Gonzalez 2017 Methods.Mol.Biol 1545 139 PubMedID: 27943212 Abstract Extracellular vesicles (EV), including exosomes, secreted vesicles of endocytic origin, and microvesicles derived from the plasma membrane, have been widely isolated and characterized from conditioned culture media and bodily fluids. The difficulty in isolating EV from tissues, however, has hindered their study in vivo. Here, we describe a novel method designed to isolate EV and characterize exosomes from the extracellular space of brain tissues. The purification of EV is achieved by gentle dissociation of the tissue to free the brain extracellular space, followed by sequential low-speed centrifugations, filtration, and ultracentrifugations. To further purify EV from other extracellular components, they are separated on a sucrose step gradient. Characterization of the sucrose step gradient fractions by electron microscopy demonstrates that this method yields pure EV preparations free of large vesicles, subcellular organelles, or debris. The level of EV secretion and content are determined by assays for acetylcholinesterase activity and total protein estimation, and exosomal identification and protein content are analyzed by Western blot and immuno-electron microscopy. Additionally, we present here a method to delipidate EV in order to improve the resolution of downstream electrophoretic analysis of EV proteins. Title: Quercetin along with piperine prevents cognitive dysfunction, oxidative stress and neuro-inflammation associated with mouse model of chronic unpredictable stress Rinwa P, Kumar A Ref: Arch Pharm Res, 40:1166, 2017 : PubMed ESTHER: Rinwa_2017_Arch.Pharm.Res_40_1166 PubMedSearch: Rinwa 2017 Arch.Pharm.Res 40 1166 PubMedID: 23856969 Abstract Stress occurs in everyday life and persistence of it causes memory loss. Bioflavonoids like quercetin are reported to have poor bioavailability and limited therapeutic potential against stress induced neurological disorders. Therefore, the present study is an attempt to elucidate the therapeutic potency of combination of quercetin with piperine; a bioavailability enhancer against chronic unpredictable stress (CUS)-induced behavioral and biochemical alterations. Laca mice were subjected to a series of stressful events for a period of 28 days. Quercetin (20, 40 and 80 mg/kg, p.o.), piperine (20 mg/kg, p.o.) and their combinations were administered daily 30 min before CUS procedure. Piracetam (100 mg/kg, i.p.) served as a standard control. CUS caused impaired spatial navigation in Morris water maze test and poor retention in elevated plus maze task. Further, there was significant increase in brain oxidative stress markers and neuro-inflammation (TNF-alpha). This was coupled with marked rise in acetylcholinesterase and serum corticosterone levels. Co-administration of piperine with quercetin significantly elevated their potential to restore these behavioral, biochemical and molecular changes associated with mouse model of CUS. These results suggest that piperine enhances the neuroprotective effects of quercetin against CUS-induced oxidative stress, neuro-inflammation and memory deficits. Title: Galantamine attenuates N,N-dimethyl hydrazine induced neoplastic colon damage by inhibiting acetylcholinesterase and bimodal regulation of nicotinic cholinergic neurotransmission Sammi SR, Rawat JK, Raghav N, Kumar A, Roy S, Singh M, Gautam S, Yadav RK, Devi U and Kaithwas G <1 more author(s)> Sammi SR, Rawat JK, Raghav N, Kumar A, Roy S, Singh M, Gautam S, Yadav RK, Devi U, Pandey R, Kaithwas G (- 1) Ref: European Journal of Pharmacology, 818:174, 2017 : PubMed ESTHER: Sammi_2017_Eur.J.Pharmacol_818_174 PubMedSearch: Sammi 2017 Eur.J.Pharmacol 818 174 PubMedID: 29074413 Abstract The present study reveals the effect of galantamine (GAL) against 1, 2-dimethylhydrazine (DMH) induced colon cancer. Wistar albino rats were arbitrarily divided into four groups (n = 8). Group 1 served as normal control (normal saline, 3ml/kg/day, p.o.); group 2, 3 and 4 received DMH (20mg/kg/week, s.c.), for 6 weeks; groups 3 and 4 also received GAL (2 and 4mg/kg/day, p.o) for 6 weeks. DMH treated rats showed decreased heart rate variability (HRV) factors, increased incidence of aberrant crypt foci (ACF), increased thiobarbituric acid reactive substances (TBARs) along with the decrease in the enzymatic activity of superoxide dismutase (SOD) and catalase. Increased levels of inflammatory marker cyclooxygenase (COX) and lipoxygenase (LOX) was also evident in DMH treated animals. The colonic surface architecture was studied using scanning electron microscopy revealed aberrant crypts(X500) and neoplastic nodules (X2000). GAL treatment helped to minimize the ACF count, restored oxidative stress and inflammatory markers favorably. To further validate our results, our study was directed to define the effect of GAL on acetylcholine neurotransmission using a simple model organism, Caenorhabditis elegans (C. elegans). Increased synaptic cholinergic transmission by GAL (32microM) was evident in the worms when studied through aldicarb assay. However, GAL (32microM) treatment negatively modulated alpha7 nicotinic acetylcholine receptor (alpha7nAch receptor), when evaluated using the levamisole assay. GAL (32microM) treatment down regulated the genomic expression of ace-1, ace-2 along with unc-29, unc-38, and unc-50 (essential components of alpha7 nAch receptor). GAL by inhibiting AchE and regulating Alpha7nACh activity can improve cholinergic neurotransmission. Title: Neuroprotective mechanism of Coenzyme Q10 (CoQ10) against PTZ induced kindling and associated cognitive dysfunction: Possible role of microglia inhibition Bhardwaj M, Kumar A Ref: Pharmacol Rep, 68:1301, 2016 : PubMed ESTHER: Bhardwaj_2016_Pharmacol.Rep_68_1301 PubMedSearch: Bhardwaj 2016 Pharmacol.Rep 68 1301 PubMedID: 27693857 Abstract BACKGROUND: Neuroinflammation, oxidative stress and mitochondrial dysfunction play a significant role to explain the pathophysiology of epilepsy. Neuroinflammation through microglia activation has been documented in epileptogenesis. Compounds which inhibit activation of glial cells have been suggested as one of the treatment approaches for the effective treatment of epilepsy. The present study has been designed to investigate the role of coenzyme Q10 and its interaction with minocycline (microglia inhibitor) against pentylenetetrazol induced kindling epilepsy. Title: 2-Phenylbenzofuran derivatives as butyrylcholinesterase inhibitors: Synthesis, biological activity and molecular modeling Delogu GL, Matos MJ, Fanti M, Era B, Medda R, Pieroni E, Fais A, Kumar A, Pintus F Ref: Bioorganic & Medicinal Chemistry Lett, 26:2308, 2016 : PubMed ESTHER: Delogu_2016_Bioorg.Med.Chem.Lett_26_2308 PubMedSearch: Delogu 2016 Bioorg.Med.Chem.Lett 26 2308 PubMedID: 26995529 Abstract A series of 2-phenylbenzofurans compounds was designed, synthesized and evaluated as cholinesterase inhibitors. The biological assay experiments showed that most of the compounds displayed a clearly selective inhibition for butyrylcholinesterase (BChE), while a weak or no effect towards acetylcholinesterase (AChE) was detected. Among these benzofuran derivatives, compound 16 exhibited the highest BChE inhibition with an IC50 value of 30.3muM. This compound was found to be a mixed-type inhibitor as determined by kinetic analysis. Moreover, molecular dynamics simulations revealed that compound 16 binds to both the catalytic anionic site (CAS) and peripheral anionic site (PAS) of BChE and it displayed the best interaction energy value, in agreement with our experimental data. Title: Effect of Capparis spinosa Linn. extract on lipopolysaccharide-induced cognitive impairment in rats Goel A, Digvijaya, Garg A, Kumar A Ref: Indian J Exp Biol, 54:126, 2016 : PubMed ESTHER: Goel_2016_Indian.J.Exp.Biol_54_126 PubMedSearch: Goel 2016 Indian.J.Exp.Biol 54 126 PubMedID: 26934780 Abstract Cognitive disorders in mankind are not uncommon. Apart from neurodegenerative diseases such as Alzheimer's (AD), various stresses also affect cognitive functions. Plants are known to be potential source of compounds that ameliorate several diseases including cognitive impairment. Here, we evaluated effect of aqueous extract of caper (Capparis spinosa) buds on lipopolysaccharide-induced cognitive impairment in rats using two different oral doses i.e. 10 (pre-treatment) and 30 mg/rat(post-treatment) through assessment of behavioural (Morris Water maze test and Y maze test), biochemical (Cholinesterase assay) and histopathological (H&E staining) parameters. Lipopolysaccharide (from E. coli) administration resulted in an increased neurodegeneration and time taken to reach the platform (in Morris water maze). The increased neurodegeneration in CA1 region of hippocampus was significantly reduced in animals which received caper bud extract; they showed marked reduction in time taken to reach the platform at both the dose levels. The experiment demonstrated that caper bud extract exhibits potential protective effect against learning and memory damage induced by chronic administration of lipopolysaccharide (175 mug/kg) for 7 days. The results suggest that the caper bud extract could be explored for its use in the treatment of cognitive disorders. Title: Disruption of N terminus long range non covalent interactions shifted temp.opt 25 degrees C to cold: Evolution of point mutant Bacillus lipase by error prone PCR Goomber S, Kumar A, Kaur J Ref: Gene, 576:237, 2016 : PubMed ESTHER: Goomber_2016_Gene_576_237 PubMedSearch: Goomber 2016 Gene 576 237 PubMedID: 26456196 Abstract Cold adapted enzymes have applications in detergent, textile, food, bioremediation and biotechnology processes. Bacillus lipases are 'generally recognized as safe' (GRAS) and hence are industrially attractive. Bacillus lipase of 1.4 subfamily are of lowest molecular weight and are reversibly unfolded due to absence of disulphide bonds. Therefore these are largely used to study energetic of protein stability that represents unfolding of native protein to fully unfolded state. In present study, metagenomically isolated Bacillus LipJ was laboratory evolved for cold adaptation by error Prone PCR. Library of variants were screened for high relative activity at low temperature of 10 degrees C compared to native protein LipJ. Point mutant sequenced as Phe19-->Leu was determined to be active at cold and was selected for extensive biochemical, biophysical characterization. Variant F19L showed its maximum activity at 10 degrees C where parent protein LipJ had 20% relative activity. Psychrophilic nature of F19L was established with about 50% relative active at 5 degrees C where native protein was frozen to act. Variant F19L showed no activity at temperature 40 degrees C and above, establishing its thermolabile nature. Thermostability studies determined mutant to be unstable above 20 degrees C and three fold decrease in its half life at 30 degrees C compared to native protein. Far UV-CD and intrinsic fluorescence study demonstrated unstable tertiary structure of point variant F19L leading to its unfolding at low temperature of 20 degrees C. Cold adaptation of mutant F19L is accompanied with increased specific activity. Mutant was catalytically more efficient with 1.3 fold increase in kcat. Homologue structure modelling predicted disruption of intersecondary hydrophobic core formed by aromatic ring of Phe19 with non polar residues placed at beta3, beta4, beta5, beta6, alphaF. Increased local flexibility of variant F19L explains molecular basis of its psychrophilic nature. Title: Point Mutation Ile137-Met Near Surface Conferred Psychrophilic Behaviour and Improved Catalytic Efficiency to Bacillus Lipase of 1.4 Subfamily Goomber S, Kumar A, Singh R, Kaur J Ref: Appl Biochem Biotechnol, 178:753, 2016 : PubMed ESTHER: Goomber_2016_Appl.Biochem.Biotechnol_178_753 PubMedSearch: Goomber 2016 Appl.Biochem.Biotechnol 178 753 PubMedID: 26520838 Abstract Bacillus lipolytic enzymes of subfamily 1.4 are industrially attractive because of its alkaline optimum pH and broad substrate specificity. The activity and stability of these enzymes for a limited temperature range (30-50 degrees C) need attention for its industrial application. In the present study, Bacillus subtilis LipJ was rationally designed for low-temperature adaptation. Small amino acids with lower volume and without side chain branches have high occurrence among psychrophilic proteins. Met residue is reported to be preferred for cold adaptation as it is thermolabile in nature and undergoes oxidation at high temperature. Therefore, the Ile137 residue, three residues downstream the catalytic residue Asp133, was substituted by Met. Biochemical study demonstrated that variant Ile137Met was optimally active at 20 degrees C whereas parent enzyme was most active at 37 degrees C. The variant retained 70-80 % relative activity at 10 degrees C where parent enzyme demonstrated low activity. Ile137Met was observed to be unstable at and above 30 degrees C. Kinetic study demonstrated increased K m and k cat values for variant referring improved catalytic efficiency but poor substrate affinity. Homolog modelling predicted lowered number of weak interactions by substituted Met137 as molecular basis of increased flexibility of variant. Hence, increased structure flexibility might be responsible for poor substrate affinity but increased molecular motion for higher catalysis at cold. Title: Computational modelling and protein-ligand interaction studies of SMlipA lipase cloned from forest metagenome Khan M, Kumar A Ref: J Mol Graph Model, 70:212, 2016 : PubMed ESTHER: Khan_2016_J.Mol.Graph.Model_70_212 PubMedSearch: Khan 2016 J.Mol.Graph.Model 70 212 PubMedID: 27770744 Abstract The understanding of the 3-dimensional enzyme structure is important for the point of protein engineering and applications. Computer-based molecular modelling is a vital tool for theoretical predication of enzyme activities and finding their substrates and inhibitors. SMlipA lipase was cloned from forest soil metagenome and characterized as broad spectrum enzyme with high stability in various organic solvents. In the present study, to understand the mechanism of SMlipA lipase and to identify the key residues involved in enzyme-substrate interaction, three dimensional-computational model of SMlipA has been generated and validated for stereo-chemical and amino-acid environment quality using appropriate programs, and further validation of the active-site architecture was achieved by performing docking studies with different ligand. The three dimensional structure created here provide a new understanding of the ligand preferences and their interaction with protein. Title: Lipase catalysis in organic solvents: advantages and applications Kumar A, Dhar K, Kanwar SS, Arora PK Ref: Biol Proced Online, 18:2, 2016 : PubMed ESTHER: Kumar_2016_Biol.Proced.Online_18_2 PubMedSearch: Kumar 2016 Biol.Proced.Online 18 2 PubMedID: 26766927 Abstract Lipases are industrial biocatalysts, which are involved in several novel reactions, occurring in aqueous medium as well as non-aqueous medium. Furthermore, they are well-known for their remarkable ability to carry out a wide variety of chemo-, regio- and enantio-selective transformations. Lipases have been gained attention worldwide by organic chemists due to their general ease of handling, broad substrate tolerance, high stability towards temperatures and solvents and convenient commercial availability. Most of the synthetic reactions on industrial scale are carried out in organic solvents because of the easy solubility of non-polar compounds. The effect of organic system on their stability and activity may determine the biocatalysis pace. Because of worldwide use of lipases, there is a need to understand the mechanisms behind the lipase-catalyzed reactions in organic solvents. The unique interfacial activation of lipases has always fascinated enzymologists and recently, biophysicists and crystallographers have made progress in understanding the structure-function relationships of these enzymes. The present review describes the advantages of lipase-catalyzed reactions in organic solvents and various effects of organic solvents on their activity. Title: Functional characterization of hypothetical proteins of Mycobacterium tuberculosis with possible esterase/lipase signature: A Cumulative in silico and in vitro approach Kumar A, Sharma A, Kaur G, Makkar P, Kaur J Ref: J Biomol Struct Dyn, 35:1226, 2016 : PubMed ESTHER: Kumar_2016_J.Biomol.Struct.Dyn_35_1226 PubMedSearch: Kumar 2016 J.Biomol.Struct.Dyn 35 1226 PubMedID: 27050490 Gene_locus related to this paper: myctu-MT1628, myctu-RV0421C, myctu-RV0519C, myctu-RV0774C, myctu-Rv1191, myctu-Rv3591c Abstract The functional aspect of several mycobacterium proteins annotated as hypothetical are yet to be discovered. In the present investigation, in silico approaches were used to predict the biological function of some of the unknown Mtb proteins, which were further validated by wet lab experiments. After screening thousands of Mtb proteins, functionally unknown hypothetical proteins Rv0421c, Rv0519c, Rv0774c, Rv1191, Rv1592c and Rv3591c were chosen on the basis of their importance in Mtb life cycle. All these proteins posses the alpha/beta-hydrolase topological fold, characteristic of lipases/esterases, with serine, aspartate, and histidine as the putative members of the catalytic triad. The catalytic serine is located in pentapeptide motif "GXSXG" and oxyanion residue is in dipeptide motif HG. To further support our observation, molecular docking was performed with conventional synthetic lipolytic substrates (pNP-esterss) and specific lipase/esterase inhibitors (tetrahydrolipstatin, PMSF). Significant docking score and strong interaction of substrates/inhibitors with these proteins revealed that these could be possible lipases/esterases. To validate the in silico studies, these genes were cloned from Mtb genome and the proteins were over-expressed in pQE-30/Escherichia coli M15 system. The expressed proteins were purified to homogeneity and enzymatic activity was determined by using pNP esters as substrate. The enzyme activity of recombinant proteins was inhibited by tetrahydrolipstatin and PMSF pre-treatment. Outcome of the present investigation provided a basic platform to analyse and characterize unknown hypothetical proteins. Title: Possible neuroprotective mechanisms of clove oil against icv-colchicine induced cognitive dysfunction Kumar A, Aggrawal A, Pottabathini R, Singh A Ref: Pharmacol Rep, 68:764, 2016 : PubMed ESTHER: Kumar_2016_Pharmacol.Rep_68_764 PubMedSearch: Kumar 2016 Pharmacol.Rep 68 764 PubMedID: 27209363 Abstract BACKGROUND: Alzheimer's disease (AD), a common neurodegenerative disorder, recognized to be a major cause of dementia. The aim of the present study was to investigate the neuroprotective mechanisms of clove oil in intracerebroventricular (icv)-colchicine induced cognitive dysfunction in rats. Title: Microbial degradation of 2,4-dichlorophenoxyacetic acid: Insight into the enzymes and catabolic genes involved, their regulation and biotechnological implications Kumar A, Trefault N, Olaniran AO Ref: Crit Rev Microbiol, 42:194, 2016 : PubMed ESTHER: Kumar_2016_Crit.Rev.Microbiol_42_194 PubMedSearch: Kumar 2016 Crit.Rev.Microbiol 42 194 PubMedID: 25058513 Abstract A considerable progress has been made to understand the mechanisms of biodegradation of 2,4-dichlorophenoxyacetic acid (2,4-D). 2,4-D biodegradation pathway has been elucidated in many microorganisms including Cupriavidus necator JMP134 (previously known as Wautersia eutropha, Ralstonia eutropha and Alcaligenes eutrophus) and Pseudomonas strains. It generally involves the side chain removal of 2,4-D by alpha-ketoglutarate-dependent 2,4-D dioxygenase (tfdA) to form 2,4-dichlorophenol (2,4-DCP); hydroxylation of 2,4-DCP by 2,4-DCP hydroxylase (tfdB) to form dichlorocatechol; ortho or meta cleavage of dichlorocatechol by chlorocatechol 1,2-dioxygenase (tfdC) to form 2,4-dichloro-cis,cis-muconate; conversion of 2,4-dichloro-cis,cis-muconate to 2-chlorodienelactone by chloromuconate cycloisomerase (tfdD); conversion of 2-chlorodienelactone to 2-chloromaleylacetate by chlorodienelactone hydrolase (tfdE) and, finally, conversion of 2-chloromaleylacetate to 3-oxoadepate via maleylacetate by chloromaleylacetate reductase and maleylacetate reductase (tfdF), respectively, which is funnelled to the tricarboxylic acid cycle. The latest review on microbial breakdown of 2,4-D, other halogenated aromatic pesticides, and related compounds was compiled by Haggblom, however, a considerable progress has been made in this area of research since then. Thus, this review focuses on the recent advancement on 2,4-D biodegradation, the enzymes, and genes involved and their biotechlogical implications. Title: Immobilization of a novel cold active esterase onto FeO approximately cellulose nano-composite enhances catalytic properties Rahman MA, Culsum U, Kumar A, Gao H, Hu N Ref: Int J Biol Macromol, 87:488, 2016 : PubMed ESTHER: Rahman_2016_Int.J.Biol.Macromol_87_488 PubMedSearch: Rahman 2016 Int.J.Biol.Macromol 87 488 PubMedID: 26976070 Abstract A novel esterase, EstH was cloned, purified and characterized from the marine bacterium Zunongwangia sp. The purified EstH showed optimum activity at 30 degrees C and pH 8.5 with approximately 50% of original activity at 0 degrees C. EstH was stable in high salt conditions (0-4.5M NaCl). To improve the characteristics and explore the possibilities for application, a new immobilization matrix, Fe3O4 approximately cellulose nano-composite, was prepared and was characterized by Fourier Transform Infrared Spectroscopy (FTIR) and Scanning Electron Microscope (SEM). Interestingly the optimal temperature of immobilized EstH elevated to 35 degrees C. Compared to its free form, immobilized EstH showed better temperature stability (48.5% compared to 22.40% at 50 degrees C after 30min), prolonged half-life (32h compared to 18h), higher storage stability ( approximately 71% activity compared to approximately 40% after 50days of storage), improved pH tolerance ( approximately 73% activity at pH 4 and 10), and, more importantly, reusability ( approximately 50% activity after 8 repetitive cycles of usage). Enzyme kinetics showed an increase in the Vmax (from 35.76 to 51.14muM/min) and Kcat (from 365s-1 to 520s-1) after immobilization. The superior catalytic properties of immobilized EstH suggest its great potential in biotechnology and industrial processes. Title: Brain cholinergic alterations in rats subjected to repeated immobilization or forced swim stress on lambda-cyhalothrin exposure Shukla RK, Gupta R, Srivastava P, Dhuriya YK, Singh A, Chandravanshi LP, Kumar A, Siddiqui MH, Parmar D and Khanna VK <1 more author(s)> Shukla RK, Gupta R, Srivastava P, Dhuriya YK, Singh A, Chandravanshi LP, Kumar A, Siddiqui MH, Parmar D, Pant AB, Khanna VK (- 1) Ref: Neurochem Int, 93:51, 2016 : PubMed ESTHER: Shukla_2016_Neurochem.Int_93_51 PubMedSearch: Shukla 2016 Neurochem.Int 93 51 PubMedID: 26746386 Abstract Role of immobilization stress (IMS), a psychological stressor and forced swim stress (FSS), a physical stressor was investigated on the neurobehavioral toxicity of lambda-cyhalothrin (LCT), a new generation type-II synthetic pyrethroid. Pre-exposure of rats to IMS (15 min/day) or FSS (3 min/day) for 28 days on LCT (3.0 mg/kg body weight, p.o.) treatment for 3 days resulted to decrease spatial learning and memory and muscle strength associated with cholinergic-muscarinic receptors in frontal cortex and hippocampus as compared to those exposed to IMS or FSS or LCT alone. Decrease in acetylcholinesterase activity, protein expression of ChAT and PKC-beta1 associated with decreased mRNA expression of CHRM2, AChE and ChAT in frontal cortex and hippocampus was also evident in rats pre-exposed to IMS or FSS on LCT treatment, compared to rats exposed to IMS or FSS or LCT alone. Interestingly, changes both in behavioral and neurochemical endpoints were marginal in rats subjected to IMS or FSS for 28 days or those exposed to LCT for 3 days alone, compared to controls. The results suggest that stress is an important contributor in LCT induced cholinergic deficits. Title: Propensity of Withania somnifera to Attenuate Behavioural, Biochemical, and Histological Alterations in Experimental Model of Stroke Sood A, Kumar A, Dhawan DK, Sandhir R Ref: Cellular Molecular Neurobiology, 36:1123, 2016 : PubMed ESTHER: Sood_2016_Cell.Mol.Neurobiol_36_1123 PubMedSearch: Sood 2016 Cell.Mol.Neurobiol 36 1123 PubMedID: 26718711 Abstract The present study was designed to evaluate the beneficial effects of Withania somnifera (WS) pre-supplementation on middle cerebral artery occlusion (MCAO) model of ischemic stroke. Ischemic stroke was induced in the rats by inserting intraluminal suture for 90 min, followed by reperfusion injury for 24 h. The animals were assessed for locomotor functions (by neurological deficit scores, narrow beam walk and rotarod test), cognitive and anxiety-like behavioural functions (by morris water maze and elevated plus maze test). MCAO animals showed significant impairment in locomotor and cognitive functions. Neurobehavioural changes were accompanied by decreased acetylcholinesterase activity, increased oxidative stress in terms of enhanced lipid peroxidation and lowered thiol levels in the MCAO animals. In addition, MCAO animals had cerebral infarcts and the presence of pycnotic nuclei. Single-photon emission computerized tomography (SPECT) of MCAO animals revealed a cerebral infarct as a hypoactive area. On the other hand, pre-supplementation with WS (300 mg/kg body weight) for 30 days to MCAO animals was effective in restoring the acetylcholinesterase activity, lipid peroxidation, thiols and attenuated MCAO induced behavioural deficits. WS significantly reduced the cerebral infarct volume and ameliorated histopathological alterations. Improved blood flow was observed in the SPECT images from the brain regions of ischemic rats pre-treated with WS. The results of the study showed a protective effect of WS supplementation in ischemic stroke and are suggestive of its potential application in stroke management. Title: Binary combinations of organophosphorus pesticides exhibit differential toxicity under oxidised and un-oxidised conditions Arora S, Kumar A Ref: Ecotoxicology & Environmental Safety, 115C:93, 2015 : PubMed ESTHER: Arora_2015_Ecotoxicol.Environ.Saf_115C_93 PubMedSearch: Arora 2015 Ecotoxicol.Environ.Saf 115C 93 PubMedID: 25682586 Abstract Acetylcholinesterase (AChE) inhibition has been demonstrated to be useful as a biomarker for exposure to organophosphorus (OP) insecticides in many environments. The objective of this study was to investigate the response of housefly (Musca domestica) head AChE (HF-AChE) exposed to five OPs as individual compounds and their binary mixtures under in vitro conditions. To examine the effects of oxidation on OP potency in the HF-AChE system, bromine water was used as an oxidisng agent. With oxidation, the sensitivity of HF-AChE to chlorpyrifos (CPF), malathion (MLT) and triazophos (TRZ) increased significantly. Monocrotophos (MCP) and profenofos (PRF) did not exhibit any significant differences in toxicity under oxidised and un-oxidised conditions. The toxicological interaction of five organophosphorus pesticides was evaluated using the concentration addition model, the combination index-isobologram equation and the toxic unit approach. All three models provided similar predictions for the 10 binary combinations of OPs under oxidised and un-oxidised conditions. In the present study, the antagonistic effects of the binary combination of OPs (CPF+PRF, CPF+MLT, MCP+MLT, PRF+MLT, MLT+TRZ and PRF+TRZ) were observed under oxidised conditions. This may be due to dispositional and/or receptor antagonism. Most of the binary combinations assayed under un-oxidised conditions exhibited synergistic responses. Triazophos showed very strong synergism in binary combinations with CPF, MCP and PRF un-oxidised conditions. In contrast, under oxidised conditions, only CPF+TRZ exhibited synergism. The results obtained indicate differential toxicity of binary combinations of OPs under oxidised and un-oxidised conditions. This information could be a valuable tool in understanding the mechanisms of OPs interactions and the interpretation of future in vivo studies with mixtures of OP insecticides. Title: Evaluation of standardized Bacopa monniera extract in sodium fluoride-induced behavioural, biochemical, and histopathological alterations in mice Balaji B, Kumar EP, Kumar A Ref: Toxicol Ind Health, 31:18, 2015 : PubMed ESTHER: Balaji_2015_Toxicol.Ind.Health_31_18 PubMedSearch: Balaji 2015 Toxicol.Ind.Health 31 18 PubMedID: 23222693 Abstract Effect of standardized Bacopa monniera (BM; family: Scrophulariaceae) extract (100 and 300 mg/kg) against sodium fluoride (NaF; 100 and 200 ppm)-induced behavioural, biochemical, and neuropathological alterations in mice was evaluated. Akinesia, rotarod (motor coordination), forced swim test (depression), open field test (anxiety), transfer latency (memory), cholinesterase (ChE), and oxidative stress (superoxide dismutase, catalase, glutathione peroxidase, and lipid peroxidation) were determined in mice treated with NaF for 30 days alone and in combination with BM. NaF induced motor incoordination, depression, and memory impairment, and these were prevented by coadministration of BM in mice. However, NaF did not alter the weight gain, feed/water consumption, and anxiety profile. Suppression of ChE levels and increased oxidative stress were observed in mice treated with NaF. Coadministration of BM significantly improved the memory, ChE levels, and antioxidant enzymes but failed to alter the fluoride levels in NaF-treated mice. Histopathological studies revealed that BM protected the neuropathological alterations induced by NaF. Title: A review on Alzheimer's disease pathophysiology and its management: an update Kumar A, Singh A, Ekavali Ref: Pharmacol Rep, 67:195, 2015 : PubMed ESTHER: Kumar_2015_Pharmacol.Rep_67_195 PubMedSearch: Kumar 2015 Pharmacol.Rep 67 195 PubMedID: 25712639 Abstract Alzheimer's disease acknowledged as progressive multifarious neurodegenerative disorder, is the leading cause of dementia in late adult life. Pathologically it is characterized by intracellular neurofibrillary tangles and extracellular amyloidal protein deposits contributing to senile plaques. Over the last two decades, advances in the field of pathogenesis have inspired the researchers for the investigation of novel pharmacological therapeutics centered more towards the pathophysiological events of the disease. Currently available treatments i.e. acetylcholinesterase inhibitors (rivastigmine, galantamine, donepezil) and N-methyl d-aspartate receptor antagonist (memantine) contribute minimal impact on the disease and target late aspects of the disease. These drugs decelerate the progression of the disease, provide symptomatic relief but fail to achieve a definite cure. While the neuropathological features of Alzheimer's disease are recognized but the intricacies of the mechanism have not been clearly defined. This lack of understanding regarding the pathogenic process may be the likely reason for the non-availability of effective treatment which can prevent onset and progression of the disease. Owing to the important progress in the field of pathophysiology in the last couple of years, new therapeutic targets are available that should render the underlying disease process to be tackled directly. In this review, authors will discusses the different aspects of pathophysiological mechanisms behind Alzheimer's disease and its management through conventional drug therapy, including modern investigational therapeutic strategies, recently completed and ongoing. Title: Effect of Licofelone-A Dual COX/5-LOX Inhibitor in Intracerebroventricular Streptozotocin-Induced Behavioral and Biochemical Abnormalities in Rats Kumar A, Sharma S, Prashar A, Deshmukh R Ref: Journal of Molecular Neuroscience, 55:749, 2015 : PubMed ESTHER: Kumar_2015_J.Mol.Neurosci_55_749 PubMedSearch: Kumar 2015 J.Mol.Neurosci 55 749 PubMedID: 25204299 Abstract The present study was designed to investigate the effect of licofelone-a dual cyclooxygenase/5-lipoxygenase (COX/5-LOX) inhibitor in intracerebroventricular streptozotocin (ICV-STZ)-induced cognitive deficit and biochemical abnormalities in rats. ICV-STZ is a widely used model of sporadic Alzheimer's disease. In this study, STZ was administered intracerebroventricular (ICV)-bilaterally 3 mg/kg in rats. The STZ-injected rats were treated with different doses of licofelone (2.5, 5, and 10 mg/kg, p.o.) for 21 days. Cognitive functions were assessed by using Morris water maze and passive avoidance task. Levels of malondialdehyde (MDA), nitrite, reduced glutathione (GSH), and acetylcholinesterase (AChE) activity were determined to check oxidative stress and cholinergic function. Cytokine levels (IL-1beta and TNF-alpha) were also determined as markers of neuroinflammation. Administration of STZ caused a significant increase in AChE activity and cognitive dysfunction. Increased oxidative stress and the proinflammatory cytokine levels were also observed following STZ administration in rats. Licofelone treatment attenuated STZ-induced cholinergic hypofunction and cognitive deficit in rats. In addition, licofelone attenuated STZ-induced oxidative stress and elevated cytokine levels. The cognitive enhancement following licofelone administration in STZ rats may be due to its ability to restore cholinergic functions or its antioxidant activity. These observed results suggest the therapeutic potential of dual COX/5-LOX inhibitors in neurodegenerative disorders associated with oxidative stress and cognitive impairment. Title: Efficacy of Cilostazol a selective phosphodiesterase-3 inhibitor in rat model of Streptozotocin diabetes induced vascular dementia Kumar A, Jaggi AS, Singh N Ref: Pharmacol Biochem Behav, 135:20, 2015 : PubMed ESTHER: Kumar_2015_Pharmacol.Biochem.Behav_135_20 PubMedSearch: Kumar 2015 Pharmacol.Biochem.Behav 135 20 PubMedID: 25987325 Abstract The present study has been designed to investigate the potential of Cilostazol a phosphodiesterase-3 (PDE-3) inhibitor in diabetes-induced vascular dementia (Vad) employing Wistar rats. A single dose of Streptozotocin (STZ) was used for the induction of diabetes and subsequent Vad in rats. Memory and learning abilities of rats were evaluated with Morris water maze (MWM) test. Serum glucose, body weight, vascular endothelial function, serum nitrite/nitrate levels, brain oxidative stress levels (viz. brain thiobarbituric acid reactive species and reduced glutathione levels), inflammatory markers (viz. brain myeloperoxidase activity and neutrophil infiltration in the brain hippocampal area) and brain acetylcholinesterase activity were also tested. Donepezil was used as positive control. Streptozotocin treated animals showed poor performance on MWM indicating impairment of learning and memory abilities with a significant reduction in body weight, vascular endothelial function, serum nitrite/nitrate levels, along with an increase in serum glucose, brain oxidative stress levels, inflammatory changes and brain acetylcholinesterase activity. Treatment with selective PDE-3 inhibitor, Cilostazol significantly attenuated, diabetes-induced impairment of learning and memory; endothelial dysfunction, and changes in various biochemical parameters. It is concluded that selective PDE-3 inhibitor, Cilostazol may be considered as the potential pharmacological agent for the management of diabetes-induced vascular dementia. Title: Neuroprotective mechanism of losartan and its interaction with nimesulide against chronic fatigue stress Kumar A, Singh B, Mishra J, Sah SP, Pottabathini R Ref: Inflammopharmacology, 23:291, 2015 : PubMed ESTHER: Kumar_2015_Inflammopharmacology_23_291 PubMedSearch: Kumar 2015 Inflammopharmacology 23 291 PubMedID: 26122818 Abstract Potential role of angiotensin-II and cyclooxygenase have been suggested in the pathophysiology of chronic fatigue stress. The present study has been designed to evaluate the neuroprotective effect of losartan and its interaction with nimesulide against chronic fatigue stress and related complications in mice. In the present study, male Laca mice (20-30 g) were subjected to running wheel activity test session (RWATS) for 6 min daily for 21 days. Losartan, nimesulide and their combinations were administered daily for 21 days, 45 min before being subjected to RWATS. Various behavioral and biochemical and neuroinflammatory mediators were assessed subsequently. 21 days RWATS treatment significantly decreased number of wheel rotations/6 min indicating fatigue stress like behaviors as compared to naive group. 21 days treatment with losartan (10 and 20 mg/kg, ip), nimesulide (5 and 10 mg/kg, po) and their combinations significantly improved behavior [increased number of wheel rotations, reversal of post-exercise fatigue, locomotor activity, antianxiety-like behavior (number of entries, latency to enter and time spent in mirror chamber), and memory performance (transfer latency in plus-maze performance task)], biochemical parameters (reduced serum corticosterone, brain lipid peroxidation, nitrite concentration, acetylcholinesterase activity, restored reduced glutathione levels and catalase activity) as compared to RWATS control. Besides, TNF-alpha, CRP levels were significantly attenuated by these drugs and their combinations as compared to control. The present study highlights the role of cyclooxygenase modulation in the neuroprotective effect of losartan against chronic fatigue stress-induced behavioral, biochemical and cellular alterations in mice. Title: Discovery of a marine-derived bis-indole alkaloid fascaplysin, as a new class of potent P-glycoprotein inducer and establishment of its structure-activity relationship Manda S, Sharma S, Wani A, Joshi P, Kumar V, Guru SK, Bharate SS, Bhushan S, Vishwakarma RA and Bharate SB <1 more author(s)> Manda S, Sharma S, Wani A, Joshi P, Kumar V, Guru SK, Bharate SS, Bhushan S, Vishwakarma RA, Kumar A, Bharate SB (- 1) Ref: Eur Journal of Medicinal Chemistry, 107:1, 2015 : PubMed ESTHER: Manda_2015_Eur.J.Med.Chem_107_1 PubMedSearch: Manda 2015 Eur.J.Med.Chem 107 1 PubMedID: 26560048 Abstract The screening of IIIM natural products repository for P-gp modulatory activity in P-gp over-expressing human adenocarcinoma LS-180 cells led to the identification of 7 natural products viz. withaferin, podophyllotoxin, 3-demethylcolchicine, agnuside, reserpine, seseberecine and fascaplysin as P-gp inducers. Fascaplysin (6a), a marine-derived bis-indole alkaloid, was the most potent among all of them, showing induction of P-gp with EC50 value of 25 nM. P-gp induction is one of the recently targeted strategy to increase amyloid-beta clearance from Alzheimer brains. Thus, we pursued a medicinal chemistry of fascaplysin to establish its structure-activity relationship for P-gp induction activity. Four series of analogs viz. substituted quaternary fascaplysin analogs, D-ring opened quaternary analogs, D-ring opened non-quaternary analogs, and beta-carbolinium analogs were synthesized and screened for P-gp induction activity. Among the total of 48 analogs screened, only quaternary nitrogen containing analogs 6a-g and 10a, 10h-l displayed promising P-gp induction activity; whereas non-planar non-quaternary analogs 9a-m, 13a-n, 15a-h were devoid of this activity. The P-gp induction activity of best compounds was then confirmed by western-blot analysis, which indicated that fascaplysin (6a) along with 4,5-difluoro analog of fascaplysin 6f and D-ring opened analog 10j displayed 4-8 fold increase in P-gp expression in LS-180 cells at 1 muM. Additionally, compounds 6a and 6f also showed inhibition of acetylcholinestease (AChE), an enzyme responsible for neuronal loss in Alzheimer's disease. Thus, fascaplysin and its analogs showing promising P-gp induction along with AChE inhibition at 1 muM, with good safety window (LS-180: IC50 > 10 muM, hGF: 4 muM), clearly indicates their promise for development as an anti-Alzheimer agent. Title: Neuroprotective effect of N-acetyl cysteine against streptozotocin-induced memory dysfunction and oxidative damage in rats Prakash A, Kalra JK, Kumar A Ref: J Basic Clin Physiol Pharmacol, 26:13, 2015 : PubMed ESTHER: Prakash_2015_J.Basic.Clin.Physiol.Pharmacol_26_13 PubMedSearch: Prakash 2015 J.Basic.Clin.Physiol.Pharmacol 26 13 PubMedID: 24756058 Abstract BACKGROUND: Growing evidences indicate that endogenous oxidants and antioxidant defense interact in a vicious cycle, which plays a critical role in the pathogenesis of cognitive dysfunction. In this study, we examined the effect of N-acetyl cysteine (NAC) against the intracerebroventricular infusion of streptozotocin (ICV STZ)-induced cognitive impairment and mitochondrial oxidative damage in rats. Title: Microglial Inhibitory Mechanism of Coenzyme Q10 Against Abeta (1-42) Induced Cognitive Dysfunctions: Possible Behavioral, Biochemical, Cellular, and Histopathological Alterations Singh A, Kumar A Ref: Front Pharmacol, 6:268, 2015 : PubMed ESTHER: Singh_2015_Front.Pharmacol_6_268 PubMedSearch: Singh 2015 Front.Pharmacol 6 268 PubMedID: 26617520 Abstract Rationale: Alzheimer's disease (AD) is a debilitating disease with complex pathophysiology. Amyloid beta (Abeta) (1-42) is a reliable model of AD that recapitulates many aspects of human AD. Objective: The intent of the present study was to investigate the neuroprotective potential of Coenzyme Q10 (CoQ10) and its modulation by minocycline (microglial inhibitor) against Abeta (1-42) induced cognitive dysfunction in rats. Method: Intrahippocampal (i.h.) Abeta (1-42) (1 mug/mul; 4mul/site) were administered followed by drug treatment with galantamine (2 mg/kg), CoQ10 (20 and 40 mg/kg), minocycline (50 and 100 mg/kg) and their combinations for a period of 21 days. Various neurobehavioral parameters followed by biochemical, acetylcholinesterase (AChE) level, proinflammatory markers (TNF-alpha), mitochondrial respiratory enzyme complexes (I-IV) and histopathological examinations were assessed. Results: Abeta (1-42) administration significantly impaired cognitive performance in Morris water maze (MWM) performance test, causes oxidative stress, raised AChE level, caused neuroinflammation, mitochondrial dysfunction and histopathological alterations as compared to sham treatment. Treatment with CoQ10 (20 and 40 mg/kg) and minocycline (50 and 100 mg/kg) alone for 21 days significantly improved cognitive performance as evidenced by reduced transfer latency and increased time spent in target quadrant (TSTQ), reduced AChE activity, oxidative damage (reduced LPO, nitrite level and restored SOD, catalase and GHS levels), TNF-alpha level, restored mitochondrial respiratory enzyme complex (I, II, III, IV) activities and histopathological alterations as compared to Abeta (1-42) treated animals. Further, combinations of minocycline (50 and 100 mg/kg) with CoQ10 (20 and 40 mg/kg) significantly modulates the protective effect of CoQ10 dose dependently as compared to their effect alone. Conclusion: The present study suggests that the neuroprotective effect of CoQ10 could be due to its microglia inhibitory mechanism along with its mitochondrial restoring and anti-oxidant properties. Title: Evaluation of Acute toxicity of Lambda Cyhalothrin in Mus musculus L Tomar M, Kumar A, Kataria SK Ref: Indian J Exp Biol, 53:551, 2015 : PubMed ESTHER: Tomar_2015_Indian.J.Exp.Biol_53_551 PubMedSearch: Tomar 2015 Indian.J.Exp.Biol 53 551 PubMedID: 26349319 Abstract Lambda Cyhalothrin (LCT) is a type II synthetic pyrethroid widely used in agriculture, home pest control and protection of food stuff. Here, we evaluated its toxicity on biochemical parameters (Total protein, Acetyl cholinesterase, RNA and DNA) and liver histological alteration in mice after 24 h of oral administration @ 25, 50 and 75% of LD50 i.e.; 26.49 mg/kg/body wt. Distilled water (DW) and Cyclophosphamide (CP @ 40 mg/kg/body wt.) were used as negative and positive control; respectively. LCT treated mice showed significant decrease in total protein (P < 0.01), acetyl cholinesterase (P < 0.001) and DNA (P < 0.001) in a dose dependent manner. On the contrary, RNA content showed significant increase (P < 0.01) at 50% of LD50 of LCT. Histological observations of the mice liver showed vascular congestion and hepatocyte degeneration with 6.63 mg/kg/body wt. of LCT; and accumulation of RBCs with sinusoid degeneration and wide necrotic area with pyknosis with 13.25 and 19.88 mg/kg/body wt., respectively. The results demonstrated LCT induced biochemical changes and hepatotoxicity in female mice. Title: A cold-adapted, solvent and salt tolerant esterase from marine bacterium Psychrobacter pacificensis Wu G, Zhang X, Wei L, Kumar A, Mao T, Liu Z Ref: Int J Biol Macromol, 81:180, 2015 : PubMed ESTHER: Wu_2015_Int.J.Biol.Macromol_81_180 PubMedSearch: Wu 2015 Int.J.Biol.Macromol 81 180 PubMedID: 26231332 Abstract Lipolytic enzymes with unique physico-chemical characteristics are gaining more attention for their immense industrial importance. In this study, a novel lipolytic enzyme (Est11) was cloned from the genomic library of a marine bacterium Psychrobacter pacificensis. The enzyme was expressed in Escherichia coli and purified to homogeneity with molecular mass of 32.9kDa. The recombinant Est11 was able to hydrolyze short chain esters (C2-C8) and displayed an optimum activity against butyrate ester (C4). The optimal temperature and pH were 25 degrees C and 7.5, respectively. Est11 retained more than 70% of its original activity at 10 degrees C, suggesting that it was a cold-active esterase. The enzyme was highly active and stable at high concentration of NaCl (5M). Further, incubation with ethanol, isopropanol, propanediol, DMSO, acetonitrile, and glycerol rendered remarkable positive effects on Est11 activity. Typically, even at the concentration of 30% (v/v), ethanol, DMSO, and propanediol increased Est11 activity by 1.3, 2.0, and 2.4-folds, respectively. This new robust enzyme with remarkable properties like cold-adaptability, exceptional tolerance to salt and organic solvents provides us a promising candidate to meet the needs of some harsh industrial processes. Title: Expression, purification, crystallization and preliminary X-ray diffraction analysis of acylpeptide hydrolase from Deinococcus radiodurans Are VN, Ghosh B, Kumar A, Yadav P, Bhatnagar D, Jamdar SN, Makde RD Ref: Acta Crystallographica F Struct Biol Commun, 70:1292, 2014 : PubMed ESTHER: Are_2014_Acta.Crystallogr.F.Struct.Biol.Commun_70_1292 PubMedSearch: Are 2014 Acta.Crystallogr.F.Struct.Biol.Commun 70 1292 PubMedID: 25195912 Gene_locus related to this paper: deira-DR0165 Abstract Acylpeptide hydrolase (APH; EC 3.4.19.1), which belongs to the S9 family of serine peptidases (MEROPS), catalyzes the removal of an N-acylated amino acid from a blocked peptide. The role of this enzyme in mammalian cells has been suggested to be in the clearance of oxidatively damaged proteins as well as in the degradation of the beta-amyloid peptides implicated in Alzheimer's disease. Detailed structural information for the enzyme has been reported from two thermophilic archaea; both of the archaeal APHs share a similar monomeric structure. However, the mechanisms of substrate selectivity and active-site accessibility are totally different and are determined by inter-domain flexibility or the oligomeric structure. An APH homologue from a bacterium, Deinococcus radiodurans (APHdr), has been crystallized using microbatch-under-oil employing the random microseed matrix screening method. The protein crystallized in space group P21, with unit-cell parameters a = 77.6, b = 189.6, c = 120.4 A, beta = 108.4 degrees . A Matthews coefficient of 2.89 A(3) Da(-1) corresponds to four monomers, each with a molecular mass of approximately 73 kDa, in the asymmetric unit. The APHdr structure will reveal the mechanisms of substrate selectivity and active-site accessibility in the bacterial enzyme. It will also be helpful in elucidating the functional role of this enzyme in D. radiodurans. Title: Mildronate improves cognition and reduces amyloid-beta pathology in transgenic Alzheimer's disease mice Beitnere U, van Groen T, Kumar A, Jansone B, Klusa V, Kadish I Ref: Journal of Neuroscience Research, 92:338, 2014 : PubMed ESTHER: Beitnere_2014_J.Neurosci.Res_92_338 PubMedSearch: Beitnere 2014 J.Neurosci.Res 92 338 PubMedID: 24273007 Abstract Mildronate, a carnitine congener drug, previously has been shown to provide neuroprotection in an azidothymidine-induced mouse model of neurotoxicity and in a Parkinson's disease rat model. The aim of this study was to investigate the effects of mildronate treatment on cognition and pathology in Alzheimer's disease (AD) model mice (APPSweDI ). Mildronate was administered i.p. daily at 50 or 100 mg/kg for 28 days. At the end of treatment, the animals were behaviorally and cognitively tested, and brains were assessed for AD-related pathology, inflammation, synaptic markers, and acetylcholinesterase (AChE). The data show that mildronate treatment significantly improved animal performance in water maze and social recognition tests, lowered amyloid-beta deposition in the hippocampus, increased expression of the microglia marker Iba-1, and decreased AChE staining, although it did not alter expression of proteins involved in synaptic plasticity (GAP-43, synaptophysin, and GAD67). Taken together, these findings indicate mildronate's ability to improve cognition and reduce amyloid-beta pathology in a mouse model of AD and its possible therapeutic utility as a disease-modifying drug in AD patients. (c) 2013 Wiley Periodicals, Inc. Title: Cloning, expression, purification and three-dimensional structure prediction of haloalkane dehalogenase from a recently isolated Ancylobacter aquaticus strain UV5 Kumar A, Pillay B, Olaniran AO Ref: Protein Expr Purif, 99C:10, 2014 : PubMed ESTHER: Kumar_2014_Protein.Expr.Purif_99C_10 PubMedSearch: Kumar 2014 Protein.Expr.Purif 99C 10 PubMedID: 24642226 Abstract Haloalkane dehalogenase (DhlA) converts 1,2-dichloroethane (1,2-DCA) to 2-chloroethane in the genus Ancylobacter and Xanthobacter autotrophicus GJ10 (XaDhlA) and allows these organisms to utilise 1,2-DCA and some other halogenated alkanes for growth. The DhlA encoding gene (dhlA) was PCR-amplified from the genomic DNA of a recently isolated Ancylobacter aquaticus UV5 strain, cloned and overexpressed in Escherichiacoli BL21 (DE3). The recombinant enzyme was purified by using Amicon ultra-15 centrifugal filter units, an anion-exchange QFF column followed by a gel-filtration column (Sephacryl HR100). Enzyme activity was determined by using 1,2-DCA as a substrate. Three-dimensional structure of the enzyme was predicted using SWISS-MODEL workspace and the biophysical properties were predicted by submitting the amino acid sequence of DhlA on ExPASy server. DhlA (Mr 35kDa) exhibited optimum activity at temperature 37 degrees C and pH 9.0. The enzyme retained approximately 50% of its activity after 1h of incubation at 50 degrees C, and showed moderate stability against denaturing agent urea. The DhlA displayed a Km value of 842muM and kcat/Km ratio of 168mM-1min-1 for its substrate 1,2-DCA. This DhlA was found to belong to the alpha/beta hydrolase family with a catalytic triad composed of Asp-His-Asp in its active site. This is the first study reporting on the characterisation and reaction kinetics of purified DhlA from A.aquaticus UV5 indigenous to contaminated site in Africa. Title: Possible nitric oxide modulation in the protective effects of rutin against experimental head trauma-induced cognitive deficits: behavioral, biochemical, and molecular correlates Kumar A, Rinwa P, Dhar H Ref: J Surg Res, 188:268, 2014 : PubMed ESTHER: Kumar_2014_J.Surg.Res_188_268 PubMedSearch: Kumar 2014 J.Surg.Res 188 268 PubMedID: 24484907 Abstract BACKGROUND: Traumatic head injury is turning out to be a major cause of disability and death. Nitric oxide (NO), an intercellular messenger plays a crucial role in the pathophysiology of several neurologic disorders. Therefore, the present study was designed to investigate the effects of rutin, a well-known flavonoid against cognitive deficits and neuroinflammation associated with traumatic head injury and the probable role of NO pathway in this effect. MATERIALS AND Title: Microglial inhibitory effect of ginseng ameliorates cognitive deficits and neuroinflammation following traumatic head injury in rats Kumar A, Rinwa P, Dhar H Ref: Inflammopharmacology, 22:155, 2014 : PubMed ESTHER: Kumar_2014_Inflammopharmacology_22_155 PubMedSearch: Kumar 2014 Inflammopharmacology 22 155 PubMedID: 24052247 Abstract Traumatic brain injury produces several neuropathological alterations, some of them are analogous to patients suffering from memory disorders. Role of neuroinflammation and oxidative stress has been suggested in the pathophysiology of brain injury-induced cognitive dysfunction. Therefore, the present study was designed to explore the possible role of ginseng and its interaction with minocycline (microglial inhibitor) against experimental brain trauma-induced behavioral, biochemical and molecular alterations. Wistar rats were exposed to brain traumatic injury using weight-drop method. Following injury and a post-injury rehabilitation period of 2 weeks, animals were administered vehicle/drugs for another 2 weeks. Brain injury caused significant memory impairment in Morris water maze task as evident from increase in escape latency and total distance travelled to reach the hidden platform. This was followed by a significant decrease in time spent in target quadrant and frequency of appearance in target quadrant. Further, there was a significant increase in oxidative stress markers, neuroinflammation (TNF-alpha and IL-6) and acetylcholinesterase levels in both cortex and hippocampal regions of traumatized rat brain. Ginseng (100 and 200 mg/kg) and minocycline (50 mg/kg) treatment for 2 weeks significantly attenuated all these behavioral, biochemical and molecular alterations. Further, combination of sub-effective doses of ginseng (50 and 100 mg/kg) and minocycline (25 mg/kg) potentiated their protective effects which was significant as compared to their effects alone. The results of the present study suggest that the therapeutic effects of ginseng might involve inhibition of microglial pathway against head trauma-induced cognitive impairment and neuroinflammation in rats. Title: Two structurally different dienelactone hydrolases (TfdEI and TfdEII) from Cupriavidus necator JMP134 plasmid pJP4 catalyse cis- and trans-dienelactones with similar efficiency Kumar A, Pillay B, Olaniran AO Ref: PLoS ONE, 9:e101801, 2014 : PubMed ESTHER: Kumar_2014_PLoS.One_9_e101801 PubMedSearch: Kumar 2014 PLoS.One 9 e101801 PubMedID: 25054964 Gene_locus related to this paper: alceu-tfe1, alceu-tfe2 Abstract In this study, dienelactone hydrolases (TfdEI and TfdEII) located on plasmid pJP4 of Cupriavidus necator JMP134 were cloned, purified, characterized and three dimensional structures were predicted. tfdEI and tfdEII genes were cloned into pET21b vector and expressed in E. coli BL21(DE3). The enzymes were purified by applying ultra-membrane filtration, anion-exchange QFF and gel-filtration columns. The enzyme activity was determined by using cis-dienelactone. The three-dimensional structure of enzymes was predicted using SWISS-MODEL workspace and the biophysical properties were determined on ExPASy server. Both TfdEI and TfdEII (Mr 25 kDa) exhibited optimum activity at 37 degrees C and pH 7.0. The enzymes retained approximately 50% of their activity after 1 h of incubation at 50 degrees C and showed high stability against denaturing agents. The TfdEI and TfdEII hydrolysed cis-dienelactone at a rate of 0.258 and 0.182 microMs(-1), with a Km value of 87 microM and 305 microM, respectively. Also, TfdEI and TfdEII hydrolysed trans-dienelactone at a rate of 0.053 microMs(-1) and 0.0766 microMs(-1), with a Km value of 84 microM and 178 microM, respectively. The TfdEI and TfdEII kcat/Km ratios were 0.12 microM(-1) s(-1) and 0.13 microM(-1) s(-1) and 0.216 microM(-1) s(-1) and 0.094 microM(-1) s(-1) for for cis- and trans-dienelactone, respectively. The kcat/Km ratios for cis-dienelactone show that both enzymes catalyse the reaction with same efficiency even though Km value differs significantly. This is the first report to characterize and compare reaction kinetics of purified TfdEI and TfdEII from Cupriavidus necator JMP134 and may be helpful for further exploration of their catalytic mechanisms. Title: In vivo protection of diisopropylphosphorofluoridate (DFP) poisoning by three bis-quaternary 2 -(hydroxyimino) -N -(pyridin-3-yl) acetamide derivatives in Swiss mice Kumar P, Swami D, Karade HN, Acharya J, Jatav PC, Kumar A, Meena MK Ref: Cellular & Molecular Biology (Noisy-le-grand), 60-3:53, 2014 : PubMed ESTHER: Kumar_2014_Cell.Mol.Biol.(Noisy-le-grand)_60-3_53 PubMedSearch: Kumar 2014 Cell.Mol.Biol.(Noisy-le-grand) 60-3 53 PubMedID: 25346249 Abstract This study reports efficacy of three bis pyridinium derivatives of 2—(hydroxyimino)— N—(pyridine—3—yl) acetamide in terms of survival, reactivation of brain and serum acetylcholinesterase (AChE) activity in diisopropylphosphorofluoridate (DFP) intoxicated Swiss albino male mice. LD50 of DFP (3.9 mg/kg, s.c.) and new oximes, HNK—102, HNK—106, HNK—111, (282.8, 35.0 and 35.0 mg/kg respectively, i.m.) was determined. Various doses of DFP and oximes as treatment doses with atropine (10 mg/kg, i.p.) were used to determine protection index (PI). For time dependent maximum AChE inhibition, two doses of DFP (0.20 and 2.0 LD50) were chosen. At optimized time i.e. Sixty minutes, IC50 value was calculated as 0.249 and 0.017 LD50 of brain and serum AChE, respectively. Shift of DFP induced brain AChE IC50 curves to right was observed at 0.20 LD50 treatment dose of oximes with respect to 2—PAM. These findings propose that new HNK series of oximes are effective antidote, compared to that of 2—PAM in vivo. Title: Rosiglitazone Synergizes the Neuroprotective Effects of Valproic Acid Against Quinolinic Acid-Induced Neurotoxicity in Rats: Targeting PPARgamma and HDAC Pathways Mishra J, Chaudhary T, Kumar A Ref: Neurotox Res, 26:130, 2014 : PubMed ESTHER: Mishra_2014_Neurotox.Res_26_130 PubMedSearch: Mishra 2014 Neurotox.Res 26 130 PubMedID: 24566814 Abstract Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disorder which affects medium spiny GABAergic neurons mainly in the striatum. Oxidative damage, neuro-inflammation, apoptosis, protein aggregation, and signaling of neurotrophic factors are some of the common cellular pathways involved in HD. Quinolinic acid (QA) causes excitotoxicity by stimulating N-methyl-D-aspartate receptors via calcium overload leading to neurodegeneration. Neuroprotective potential of peroxisome proliferator activated receptor-gamma (PPARgamma) agonists and histone deacetylase (HDAC) inhibitors have been well documented in experimental models of neurodegenerative disorders; however, their exact mechanisms are not clear. Therefore, present study has been designed to explore possible neuroprotective mechanism of valproic acid (VPA) and its interaction with rosiglitazone against QA induced HD-like symptoms in rats. Single bilateral intrastriatal QA (200 nmol/2 mul saline) administration significantly caused motor incoordination, memory impairment, oxidative damage, mitochondrial dysfunction (complex I, II, II and IV), cellular alterations [tumor necrosis factor-alpha (TNF-alpha), caspase-3, brain derived neurotrophic factor, acetylcholinesterase], and striatal neurodegeneration as compared to sham group. Treatment with rosiglitazone (5, 10 mg/kg) and VPA (100, 200 mg/kg) for 21 days significantly attenuated these behavioral, biochemical, and cellular alterations as compared to control (QA 200 nmol) group. However, VPA (100 mg/kg) treatment in combination with rosiglitazone (5 mg/kg) for 21 days synergized their neuroprotective effect, which was significant as compared to their effects per se in QA-treated animals. The present study provides an evidence of possible interplay of PPARgamma agonists and HDAC inhibitors as a novel therapeutic strategy in the management of HD. Title: Implicating the role of lycopene in restoration of mitochondrial enzymes and BDNF levels in beta-amyloid induced Alzheimers disease Prakash A, Kumar A Ref: European Journal of Pharmacology, 741C:104, 2014 : PubMed ESTHER: Prakash_2014_Eur.J.Pharmacol_741C_104 PubMedSearch: Prakash 2014 Eur.J.Pharmacol 741C 104 PubMedID: 25066110 Abstract Lycopene has attracted significant research interest due to its beneficial therapeutic effects, which include anti-oxidant, neuro-protective and anti-cancer effects, but the mechanisms of its beneficial action are not clear so far. The present study was carried out to elucidate the neuroprotective effect of lycopene against the beta-amyloid induced cognitive impairment and mitochondria oxidative damage in rats. beta-amyloid (beta-A1-42) was administered through intracerebroventricular (ICV) by using stereotaxic instrument in male Wistar rats. Lycopene (2.5 and 5mg/kg) was administrated for three weeks. Behavioral performances were conducted during the study. The rats were sacrificed on the 21st day following the last behavioral test and cytoplasmic fractions of hippocampus were prepared for the quantification of acetylcholinesterase, oxidative stress parameter, mitochondrial enzymes, and inflammatory mediator like TNF-alpha, Il-6 activities, caspase-3 and BDNF. ICV beta-A1-42 resulted in poor memory retention in Morris water maze and caused marked oxidative stress as indicated by significant increase in oxidative, mitochondria damage, TNF-alpha, IL-6 and Caspase-3 activity. We also found that beta-A1-42 induced animal altered BDNF level than control animals. Chronic administration of lycopene resulted in an improvement in memory retention, attenuation of mitochondrial-oxidative damage, reduced neuro-inflammation and restoration of BDNF level in beta-A1-42 treated rats. These studies indicated that lycopene helps to protect beta-A1-42 induced cognitive dysfunction and modulates amyloidogenesis. Title: Modulation of nitrergic signalling pathway by American ginseng attenuates chronic unpredictable stress-induced cognitive impairment, neuroinflammation, and biochemical alterations Rinwa P, Kumar A Ref: Naunyn Schmiedebergs Arch Pharmacol, 387:129, 2014 : PubMed ESTHER: Rinwa_2014_Naunyn.Schmiedebergs.Arch.Pharmacol_387_129 PubMedSearch: Rinwa 2014 Naunyn.Schmiedebergs.Arch.Pharmacol 387 129 PubMedID: 24132508 Abstract Prolonged stress causes extensive loss of neurons leading to deficits in cognitive performance. Increasing evidence indicates that accumulation of intercellular messenger, nitric oxide (NO), plays a crucial role in the pathogenesis of memory disorders. American ginseng (AG) is known to show protection in different animal models of neurological diseases; however, its exact mechanism of action is not clearly understood. Therefore, the current study was designed to investigate the interaction of AG against chronic unpredictable stress (CUS)-associated behavioral and biochemical alterations and the probable role of nitrergic pathway in this effect. Male Laca mice were exposed to a series of stressors along with drug/vehicle treatment daily for 28 days. CUS paradigm caused significant impairment in both acquisition and retention memory as measured in Morris water maze and elevated plus maze task. This was coupled with alterations in oxidative stress markers, mitochondrial enzyme complex activities, pro-inflammatory cytokine (TNF-alpha), and acetylcholinesterase levels in the hippocampus as compared with naive group. Besides, there was a marked increase in serum corticosterone levels. AG (100, 200 mg/kg; p.o.) treatment significantly improved cognitive impairment; reduced TNF-alpha, acetylcholinesterase, and corticosterone levels; and attenuated oxidative-nitrergic stress. Furthermore, pre-treatment of L-arginine (100 mg/kg; i.p.), a nitric oxide donor, with subeffective dose of AG (100 mg/kg; p.o.) reversed its protective effects. However, L-NAME (10 mg/kg, i.p.), a non-specific NO synthase inhibitor, potentiated the effects of AG. Our findings suggest that modulation of nitrergic signalling cascade is involved in the protective effects of AG against CUS-induced cognitive dysfunction, oxidative stress, and neuroinflammation. Title: Recent advances in industrial application of tannases: a review Beniwal V, Kumar A, Sharma J, Chhokar V Ref: Recent Pat Biotechnol, 7:228, 2013 : PubMed ESTHER: Beniwal_2013_Recent.Pat.Biotechnol_7_228 PubMedSearch: Beniwal 2013 Recent.Pat.Biotechnol 7 228 PubMedID: 24182319 Abstract Tannin acyl hydrolase (E.C. 3.1.1.20) commonly referred as tannase, is a hydrolytic enzyme that catalyses the hydrolysis of ester bonds present in gallotannins, ellagitannins, complex tannins and gallic acid esters. Tannases are the important group of botechnologically relevant enzymes distributed throughout the animal, plant and microbial kingdoms. However, microbial tannases are currently receiving a great deal of attention. Tannases are extensively used in food, feed, pharmaceutical, beverage, brewing and chemical industries. Owing to its diverse area of applications, a number of patents have been appeared in the recent past. The present review pretends to present the advances and perspectives in the industrial application of tannase with special emphasis on patents. Title: Characterization of bud emergence 46 (BEM46) protein: Sequence, structural, phylogenetic and subcellular localization analyses Kumar A, Kollath-Leiss K, Kempken F Ref: Biochemical & Biophysical Research Communications, 438:526, 2013 : PubMed ESTHER: Kumar_2013_Biochem.Biophys.Res.Commun_438_526 PubMedSearch: Kumar 2013 Biochem.Biophys.Res.Commun 438 526 PubMedID: 23916612 Gene_locus related to this paper: neucr-q7sdx9 Abstract The bud emergence 46 (BEM46) protein from Neurospora crassa belongs to the alpha/beta-hydrolase superfamily. Recently, we have reported that the BEM46 protein is localized in the perinuclear ER and also forms spots close by the plasma membrane. The protein appears to be required for cell type-specific polarity formation in N. crassa. Furthermore, initial studies suggested that the BEM46 amino acid sequence is conserved in eukaryotes and is considered to be one of the widespread conserved "known unknown" eukaryotic genes. This warrants for a comprehensive phylogenetic analysis of this superfamily to unravel origin and molecular evolution of these genes in different eukaryotes. Herein, we observe that all eukaryotes have at least a single copy of a bem46 ortholog. Upon scanning of these proteins in various genomes, we find that there are expansions leading into several paralogs in vertebrates. Usingcomparative genomic analyses, we identified insertion/deletions (indels) in the conserved domain of BEM46 protein, which allow to differentiate fungal classes such as ascomycetes from basidiomycetes. We also find that exonic indels are able to differentiate BEM46 homologs of different eukaryotic lineage. Furthermore, we unravel that BEM46 protein from N. crassa possess a novel endoplasmic-retention signal (PEKK) using GFP-fusion tagging experiments. We propose that three residues namely a serine 188S, a histidine 292H and an aspartic acid 262D are most critical residues, forming a catalytic triad in BEM46 protein from N. crassa. We carried out a comprehensive study on bem46 genes from a molecular evolution perspective with combination of functional analyses. The evolutionary history of BEM46 proteins is characterized by exonic indels in lineage specific manner. Title: Identification and characterisation of small-molecule inhibitors of Rv3097c-encoded lipase (LipY) of Mycobacterium tuberculosis that selectively inhibit growth of bacilli in hypoxia Saxena AK, Roy KK, Singh S, Vishnoi SP, Kumar A, Kashyap VK, Kremer L, Srivastava R, Srivastava BS Ref: Int J Antimicrob Agents, 42:27, 2013 : PubMed ESTHER: Saxena_2013_Int.J.Antimicrob.Agents_42_27 PubMedSearch: Saxena 2013 Int.J.Antimicrob.Agents 42 27 PubMedID: 23684389 Gene_locus related to this paper: myctu-Rv3097c Inhibitor(s) related to this paper: Cpd8f-quinoline-carboxamide Abstract The mycobacterial Rv3097c-encoded lipase LipY is considered as a true lipase involved in the hydrolysis of triacylglycerol stored in lipid inclusion bodies for the survival of dormant mycobacteria. To date, orlistat is the only known LipY inhibitor. In view of the important emerging role of this enzyme, a search for small-molecule inhibitors of LipY was made, leading to the identification of some new compounds (8a-8d, 8f, 8h and 8i) with potent inhibitory activities against recombinant LipY, with no cytotoxicity [50% inhibitory concentration (CC(50)) 500 g/mL]. The compounds 6a, 8c and 8f potently inhibited (>90%) the growth of Mycobacterium tuberculosis H37Rv grown under hypoxia (oxygen-depleted condition) but had no effect on aerobically grown bacilli, suggesting that these new small molecules are highly selective towards the growth inhibition of hypoxic cultures of M. tuberculosis and hence provide new leads for combating latent tuberculosis. Title: The genome and development-dependent transcriptomes of Pyronema confluens: a window into fungal evolution Traeger S, Altegoer F, Freitag M, Gabaldon T, Kempken F, Kumar A, Marcet-Houben M, Poggeler S, Stajich JE, Nowrousian M Ref: PLoS Genet, 9:e1003820, 2013 : PubMed ESTHER: Traeger_2013_PLoS.Genet_9_E1003820 PubMedSearch: Traeger 2013 PLoS.Genet 9 E1003820 PubMedID: 24068976 Gene_locus related to this paper: pyrom-u4ltg1, pyrom-u4lhe1, pyrom-u4kwa3, pyrom-u4lfu9, pyrom-u4l0a5, pyrom-u4l0n5, pyrom-u4lhv4, pyrom-u4l8w9, pyrom-u4lvb8, pyrom-u4l9c9, pyrom-u4lwe6, pyrom-u4l3n9 Abstract Fungi are a large group of eukaryotes found in nearly all ecosystems. More than 250 fungal genomes have already been sequenced, greatly improving our understanding of fungal evolution, physiology, and development. However, for the Pezizomycetes, an early-diverging lineage of filamentous ascomycetes, there is so far only one genome available, namely that of the black truffle, Tuber melanosporum, a mycorrhizal species with unusual subterranean fruiting bodies. To help close the sequence gap among basal filamentous ascomycetes, and to allow conclusions about the evolution of fungal development, we sequenced the genome and assayed transcriptomes during development of Pyronema confluens, a saprobic Pezizomycete with a typical apothecium as fruiting body. With a size of 50 Mb and ~13,400 protein-coding genes, the genome is more characteristic of higher filamentous ascomycetes than the large, repeat-rich truffle genome; however, some typical features are different in the P. confluens lineage, e.g. the genomic environment of the mating type genes that is conserved in higher filamentous ascomycetes, but only partly conserved in P. confluens. On the other hand, P. confluens has a full complement of fungal photoreceptors, and expression studies indicate that light perception might be similar to distantly related ascomycetes and, thus, represent a basic feature of filamentous ascomycetes. Analysis of spliced RNA-seq sequence reads allowed the detection of natural antisense transcripts for 281 genes. The P. confluens genome contains an unusually high number of predicted orphan genes, many of which are upregulated during sexual development, consistent with the idea of rapid evolution of sex-associated genes. Comparative transcriptomics identified the transcription factor gene pro44 that is upregulated during development in P. confluens and the Sordariomycete Sordaria macrospora. The P. confluens pro44 gene (PCON_06721) was used to complement the S. macrospora pro44 deletion mutant, showing functional conservation of this developmental regulator. Title: Effect of nonselective and selective COX-2 inhibitors on memory dysfunction, glutathione system, and tumor necrosis factor alpha level against cerebral ischemia reperfusion injury Gaur V, Kumar A Ref: Drug & Chemical Toxicology, 35:218, 2012 : PubMed ESTHER: Gaur_2012_Drug.Chem.Toxicol_35_218 PubMedSearch: Gaur 2012 Drug.Chem.Toxicol 35 218 PubMedID: 21995864 Abstract Involvement of the glutathione system is well established in stroke-induced memory dysfunction. The aim of the present study was to investigate the effects of celecoxib (a selective cyclooxygenase-2 [COX-2] inhibitor), nimesulide (a preferential COX-2 inhibitor), and ibuprofen (a nonselective COX-2 inhibitor) against bilateral common carotid artery occlusion (BCCAO)-induced memory dysfunction. BCCAO for 30 minutews, followed by 24-hour reperfusion, significantly delayed transfer latency in the plus-maze performance task and shortened fall-off time in the hanging-wire experimental test. Besides significant alterations in glutathione defense (i.e., glutathione S-transferase and redox ratio), increased acetylcholinesterase activity and proinflammatory marker (tumor necrosis factor alpha TNF-alpha) in the hippocampus was seen. Seven days of treatment with celecoxib (3 and 10 mg/kg, p.o.), nimesulide (10 mg/kg, p.o.), and ibuprofen (30 mg/kg, p.o.) significantly improved behavioral alterations and glutathione defense and attenuated acetylcholinesterase activity and TNF-alpha levels, as compared to the control (i.e., ischemic reperfusion) group. The present study highlights the neuroprotective effect of celecoxib and nimesulide against ischemia reperfusion injury-induced memory dysfunction, neuroinflammation, and oxidative damage. Title: Whole-genome sequence of Corynebacterium pseudotuberculosis strain Cp162, isolated from camel Hassan SS, Schneider MP, Ramos RT, Carneiro AR, Ranieri A, Guimaraes LC, Ali A, Bakhtiar SM, Pereira Ude P and Silva A <23 more author(s)> Hassan SS, Schneider MP, Ramos RT, Carneiro AR, Ranieri A, Guimaraes LC, Ali A, Bakhtiar SM, Pereira Ude P, dos Santos AR, Soares Sde C, Dorella F, Pinto AC, Ribeiro D, Barbosa MS, Almeida S, Abreu V, Aburjaile F, Fiaux K, Barbosa E, Diniz C, Rocha FS, Saxena R, Tiwari S, Zambare V, Ghosh P, Pacheco LG, Dowson CG, Kumar A, Barh D, Miyoshi A, Azevedo V, Silva A (- 23) Ref: Journal of Bacteriology, 194:5718, 2012 : PubMed ESTHER: Hassan_2012_J.Bacteriol_194_5718 PubMedSearch: Hassan 2012 J.Bacteriol 194 5718 PubMedID: 23012291 Gene_locus related to this paper: corpf-d8klx9, corpf-d8kp20 Abstract Corynebacterium pseudotuberculosis is a pathogen of great veterinary and economic importance, since it affects livestock, mainly sheep and goats, worldwide, together with reports of its presence in camels in several Arabic, Asiatic, and East and West African countries, as well as Australia. In this article, we report the genome sequence of Corynebacterium pseudotuberculosis strain Cp162, collected from the external neck abscess of a camel in the United Kingdom. Title: Exploring the role of BCHE in the onset of Diabetes, Obesity and Neurological Disorders Rao AA, Jyothsna G, Shalini P, Kumar A, Bhattacharya A, Kashyap A Ref: Bioinformation, 8:276, 2012 : PubMed ESTHER: Rao_2012_Bioinformation_8_276 PubMedSearch: Rao 2012 Bioinformation 8 276 PubMedID: 22493536 Abstract Diabetes, Obesity and Neurological disturbances, most often show co-occurrence. There has been an extensive research in this domain, but the exact mechanism underlying the co-occurrence of the three conditions is still an enigma. The current paper is an approach to establish the role of Butyryl cholinesterase (BCHE) in Diabetes, Obesity and Neurological disorders by performing a comparative analysis with Neuroligin (NLGN2) a protein belonging to the same family. BCHE has its role in glucose regulation, Lipid metabolism and nerve signaling. Emphasis is laid on BCHE's diverse functions whose impediment affects the above mentioned metabolic pathways. Insilco techniques were employed to analyze the sequence, structural and functional similarities of the two proteins. A point mutation is focused which is common to both BCHE and Neuroligin. The mutation occurs at the homologous position in both the proteins making them deficient. This affects the three metabolic pathways leading to the respective disorders. The work describes the pathway that describes the role of BCHE in the onset of obesity mediated diabetes. The pathway further explains the association between Diabetes, Obesity and neurological disturbances. Title: Piperine potentiates the protective effects of curcumin against chronic unpredictable stress-induced cognitive impairment and oxidative damage in mice Rinwa P, Kumar A Ref: Brain Research, 1488:38, 2012 : PubMed ESTHER: Rinwa_2012_Brain.Res_1488_38 PubMedSearch: Rinwa 2012 Brain.Res 1488 38 PubMedID: 23099054 Abstract Life event stressors are the major vulnerability factors for the development of cognitive disorders. A vital therapeutic for stress related disorders is curcumin, derived from curry spice turmeric. Dietary phytochemicals are currently used as an adjuvant therapy to accelerate their therapeutic efficacy. Therefore, the present study was designed to investigate the effect of curcumin and its co-administration with piperine against chronic unpredictable stress (CUS)-induced cognitive impairment and oxidative stress in mice. Male Laca mice were subjected to undergo a battery of stressors for a period of 28 days. Vehicle/drugs were administered daily 30mins before CUS procedure. Chronic stress significantly impaired memory performance (delayed latency time to reach platform in Morris water maze as well as to reach closed arm in elevated plus maze test) and decreased locomotor activity along with sucrose consumption. Further, there was a significant impairment in oxidative parameters (elevated malondialdehyde, nitrite concentration and decreased reduced glutathione, catalase levels) and mitochondrial enzyme complex activities, along with raised acetylcholinesterase and serum corticosterone levels. Chronic treatment with curcumin (200 and 400mg/kg, p.o.) significantly improved these behavioral and biochemical alterations, restored mitochondrial enzyme complex activities and attenuated increased acetylcholinesterase and serum corticosterone levels. In addition, co-administration of piperine (20mg/kg; p.o.) with curcumin (100 and 200mg/kg, p.o.) significantly elevated the protective effect as compared to their effects alone. The results clearly suggest that piperine enhanced the bioavailability of curcumin and potentiated its protective effects against CUS induced cognitive impairment and associated oxidative damage in mice. Title: Synthesis of ethyl ferulate in organic medium using celite-immobilized lipase Kumar A, Kanwar SS Ref: Bioresour Technol, 102:2162, 2011 : PubMed ESTHER: Kumar_2011_Bioresour.Technol_102_2162 PubMedSearch: Kumar 2011 Bioresour.Technol 102 2162 PubMedID: 21041076 Abstract In the present work we have evaluated synthesis of ethyl ferulate by the esterification reaction of ferulic acid and ethanol catalyzed by a commercial lipase (Steapsin) immobilized onto celite-545 in a short period of 6h in DMSO. The immobilized lipase was treated with cross-linking agent glutaraldehyde (1%; v/v). The optimum synthesis of ethyl ferulate was recorded at 45 degrees C, pH 8.5 and 1:1 ratio of ethanol and ferulic acid. Co(2+), Ba(2+)and Pb(2+) ions enhanced the synthesis of ethyl ferulate Hg(2+), Cd(3+)and NH(4+) ions had mild inhibitory effect. The celite-bound lipase produced 68 mM of ethyl ferulate under optimized reaction conditions. Title: Identification of variables and value optimization for optimum lipase production by Bacillus pumilus RK31 using statistical methodology Kumar R, Mahajan S, Kumar A, Singh D Ref: N Biotechnol, 28:65, 2011 : PubMed ESTHER: Kumar_2011_N.Biotechnol_28_65 PubMedSearch: Kumar 2011 N.Biotechnol 28 65 PubMedID: 20601261 Abstract In an effort to optimize the medium components, the statistical methodology was applied to achieve the optimum lipase production under shake flask conditions. The study was conducted in three steps on newly isolated Bacillus pumilus RK 31. In the first step, 12 different variables viz., Glucose, Olive oil, Yeast extract, Peptone, Tween 80, KH(2)PO(4), MgSO(4), NaNO(3), CaCl(2), Temperature, pH and Inoculum size were used to identify the most significant variables affecting lipase production using Plackett-Burman statistical design. Variance analysis showed that Olive oil, Tween 80 and KH(2)PO(4) played significant role in lipase production. In the second step, the values of the above-identified three variables were optimized by central composite design using three-level-three-factor approach. The optimum values of Olive oil, Tween 80 and KH(2)PO(4) were found to be 10.0ml/l, 5.0ml/l and 8.0g/l, respectively. KH(2)PO(4) was found to be responsible for maximum lipase production of 5.59IU/ml, experimental and 5.03IU/ml, predicted. In the third step, the optimum predicted values of the three factors and lipase production were verified by experimental approach. The amount of lipase produced in the designated medium was in agreement with that of predicted values by statistical method. Title: Neuroprotective effect of carvedilol against aluminium induced toxicity: possible behavioral and biochemical alterations in rats Kumar A, Prakash A, Dogra S Ref: Pharmacol Rep, 63:915, 2011 : PubMed ESTHER: Kumar_2011_Pharmacol.Rep_63_915 PubMedSearch: Kumar 2011 Pharmacol.Rep 63 915 PubMedID: 22001979 Abstract Aluminium, is a trace element available in the Earth's crust naturally and has a toxic potential for humans. It has been suggested as a contributing factor in the pathogenesis of Alzheimer's disease. beta-Adrenoceptor blocking agents (beta-blockers) have been established as therapeutics for the treatment of patients with hypertension, ischemic heart diseases, chronic heart failure, arrhythmias and glaucoma. Over the years, however, beta-blockers have been associated with an incidence, albeit low, of central nervous system (CNS) side effects. In addition, noradrenergic receptors play a modulatory role in many nerve functions, including vigilance, attention, reward, learning and memory. Therefore, the present study has been designed to explore the possible role of carvedilol, an adrenergic antagonist against aluminium chloride-induced neurotoxicity in rats. Aluminium chloride (100 mg/kg) was administered daily for six weeks that significantly increased cognitive dysfunction in the Morris water maze and oxidative damage as indicated by a rise in lipid peroxidation and nitrite concentration and depleted reduced glutathione, superoxide dismutase, catalase and glutathione S-transferase activity compared to sham treatment. Chronic aluminium chloride treatment also significantly increased acetylcholinesterase activity and the aluminium concentration in brain compared to sham. Chronic administration of carvedilol (2.5 and 5 mg/kg, po) daily to rats for a period of 6 weeks significantly improved the memory performance tasks of rats in the Morris water maze test, attenuated oxidative stress (reduced lipid peroxidation, nitrite concentration and restored reduced glutathione, superoxide dismutase, catalase and glutathione S-transferase activity), decreased acetylcholinesterase activity and aluminium concentration in aluminium-treated rats compared to control rats (p < 0.05). Results of this study demonstrated the neuroprotective potential of carvedilol in aluminium chloride-induced cognitive dysfunction and oxidative damage. Title: A case of organophosphate poisoning presenting with seizure and unavailable history of parenteral suicide attempt Pandit V, Seshadri S, Rao SN, Samarasinghe C, Kumar A, Valsalan R Ref: J Emerg Trauma Shock, 4:132, 2011 : PubMed ESTHER: Pandit_2011_J.Emerg.Trauma.Shock_4_132 PubMedSearch: Pandit 2011 J.Emerg.Trauma.Shock 4 132 PubMedID: 21633583 Abstract Organophosphate (OP) poisoning is common in India. Only few case reports of parenteral OP poisoning have been described. We report a case of self-injected methyl parathion poisoning, presenting after four days with seizure, altered sensorium, and respiratory distress which posed a diagnostic and therapeutic dilemma. Despite nonavailability of history of OP poisoning, he was treated based on suspicion and showed a good clinical response to treatment trial with atropine and pralidoxime, and had a successful recovery. Atypical presentations may be encountered following parenteral administration of OP poison, and even a slight suspicion of this warrants proper investigations and treatment for a favorable outcome. Persistently low plasma cholinesterase level is a useful marker for making the diagnosis. Title: The lin genes for gamma-hexachlorocyclohexane degradation in Sphingomonas sp. MM-1 proved to be dispersed across multiple plasmids Tabata M, Endo R, Ito M, Ohtsubo Y, Kumar A, Tsuda M, Nagata Y Ref: Biosci Biotechnol Biochem, 75:466, 2011 : PubMed ESTHER: Tabata_2011_Biosci.Biotechnol.Biochem_75_466 PubMedSearch: Tabata 2011 Biosci.Biotechnol.Biochem 75 466 PubMedID: 21389627 Gene_locus related to this paper: sphpi-linb Abstract A gamma-hexachlorocyclohexane (HCH)-degrading bacterium, Sphingomonas sp. MM-1, was isolated from soil contaminated with HCH isomers. Cultivation of MM-1 in the presence of gamma-HCH led to the detection of five gamma-HCH metabolites, gamma-pentachlorocyclohexene, 2,5-dichloro-2,5-cyclohexadiene-1,4-diol, 2,5-dichlorohydroquinone, 1,2,4-trichlorobenzene, and 2,5-dichlorophenol, strongly suggesting that MM-1 has the lin genes for gamma-HCH degradation originally identified in the well-studied gamma-HCH-degrading strain Sphingobium japonicum UT26. Southern blot, PCR amplification, and sequencing analyses indicated that MM-1 has seven lin genes for the conversion of gamma-HCH to beta-ketoadipate (six structural genes, linA to linF, and one regulatory gene, linR). MM-1 carried four plasmids, of 200, 50, 40, and 30 kb. Southern blot analysis revealed that all seven lin genes were dispersed across three of the four plasmids, and that IS6100, often found close to the lin genes, was present on all four plasmids. Title: A novel amperometric biosensor based on single walled carbon nanotubes with acetylcholine esterase for the detection of carbaryl pesticide in water Firdoz S, Ma F, Yue X, Dai Z, Kumar A, Jiang B Ref: Talanta, 83:269, 2010 : PubMed ESTHER: Firdoz_2010_Talanta_83_269 PubMedSearch: Firdoz 2010 Talanta 83 269 PubMedID: 21035674 Abstract Amperometric biosensor is fabricated for the detection of carbaryl based on single walled carbon nanotubes (SWCNTs) and acetylcholine esterase (AchE). The dispersion of SWCNTs in positively charged polyelectrolyte, poly(diallyldimethylammonium chloride) (PDDA), possibly takes place due to weak supramolecular interaction between them, which then binds electrostatically to the negatively charged AchE at pH 7.4 using layer-by-layer (LbL) self-assembly technique. The optical intensity of UV/vis spectra increased with the number of layers, indicating the build up of a multilayer coating on the electrode. The activity of acetylcholine esterase on modified electrode of 3mm in diameter was found to be 0.2U. The biosensor showed good sensitivity and stability towards the monitoring of carbaryl pesticides in water with the detection limit of 10(-12)gL(-1) and recovery of 99.8 +/- 2.7% to 10(-10)gL(-1). This protocol can be used for the immobilization of other enzymes to fabricate a range of biosensors. Title: Protective effect of naringin, a citrus flavonoid, against colchicine-induced cognitive dysfunction and oxidative damage in rats Kumar A, Dogra S, Prakash A Ref: J Med Food, 13:976, 2010 : PubMed ESTHER: Kumar_2010_J.Med.Food_13_976 PubMedSearch: Kumar 2010 J.Med.Food 13 976 PubMedID: 20673063 Abstract Alzheimer's disease is a neurodegenerative disorder. Central administration of colchicine is well known to cause cognitive impairment and oxidative damage, which simulates sporadic dementia of the Alzheimer type in humans. The present study has been designed to investigate the protective effects of naringin against the colchicine-induced cognitive impairment and oxidative damage in rats. Colchicine (15 microg/5 microL), administered intracerebroventricularly, resulted in poor memory retention in both the Morris water maze and elevated plus maze task paradigms and caused marked oxidative damage. It also caused a significant decrease in acetylcholinesterase activity. Naringin (40 and 80 mg/kg, p.o.) treatment was given daily for a period of 25 days beginning 4 days prior to colchicine administration. Chronic treatment with naringin caused significant improvement in the cognitive performance and attenuated oxidative damage, as evidenced by lowering of malondialdehyde level and nitrite concentration and restoration of superoxide dismutase, catalase, glutathione S-transferase, and reduced glutathione levels, and acetylcholinesterase activity compared to control. The present study highlights the therapeutic potential of naringin against colchicine-induced cognitive impairment and associated oxidative damage. Title: Response and recovery of acetylcholinesterase activity in freshwater shrimp, Paratya australiensis (Decapoda: Atyidae) exposed to selected anti-cholinesterase insecticides Kumar A, Doan H, Barnes M, Chapman JC, Kookana RS Ref: Ecotoxicology & Environmental Safety, 73:1503, 2010 : PubMed ESTHER: Kumar_2010_Ecotoxicol.Environ.Saf_73_1503 PubMedSearch: Kumar 2010 Ecotoxicol.Environ.Saf 73 1503 PubMedID: 20701973 Abstract The toxicity of carbaryl, chlorpyrifos, dimethoate and profenofos to the freshwater shrimp, Paratya australiensis was assessed by measuring acetylcholinesterase (AChE) inhibition after 96h exposures. Shrimp exposed to these pesticides exhibited significant AChE inhibition, with mortality in shrimp corresponding to 70-90% AChE inhibition. The sensitivity of P. australiensis to the four pesticides based on AChE inhibition can be given as chlorpyrifos > profenofos > carbaryl > dimethoate. Recovery of AChE activity was followed in shrimp after 96 h exposures to carbaryl, chlorpyrifos and dimethoate. Recovery after exposure to the carbamate pesticide carbaryl was more rapid than for the two organophosphorus pesticides, chlorpyrifos and dimethoate. The slow recovery of depressed AChE activity may mean that affected organisms in the natural system are unable to sustain physical activities such as searching for food or eluding predators. To investigate the ecological significance of AChE inhibition, chemotaxis behaviour was assessed in shrimp exposed to profenofos for 24h. Abnormal chemotaxis behaviour in the exposed shrimp was observed at concentrations representing 30-50% AChE inhibition. A clear relationship existed between the depression of AChE activity and observed chemotaxis responses, such as approaching and grasping the chemoattractant source. These results suggest that in vivo toxicity tests based on this specific biomarker are sensitive and present advantages over conventional acute tests based on mortality. Behavioural studies of test organisms conducted in conjunction with measurement of AChE inhibition will provide data to clarify the toxic effects caused by sublethal chemical concentrations of anti-cholinesterase compounds. Title: Lipase-catalyzed production of a bioactive fatty amide derivative of 7,10-dihydroxy-8(E)-octadecenoic acid Khare SK, Kumar A, Kuo TM Ref: Bioresour Technol, 100:1482, 2009 : PubMed ESTHER: Khare_2009_Bioresour.Technol_100_1482 PubMedSearch: Khare 2009 Bioresour.Technol 100 1482 PubMedID: 18793843 Abstract Enzymatic syntheses of fatty amides are of considerable interest due to their wide ranging industrial applications in detergents, shampoo, cosmetics and surfactant formulations. Amidation reaction of Candida antarctica lipase B (CALB) was investigated for direct amidation of carboxylic acid in organic solvent. CALB-mediated production of a novel secondary amide was carried out by reacting the hydroxy oleic acid derivative, 7,10-dihydroxy-8(E)-octadecenoic acid (DOD), with N-methylethanol amine in organic solvent medium. A single, new product peak corresponding to the secondary amide of DOD (D2AM) was detected by high-performance liquid chromatography and thin-layer chromatography. The production of D2AM was achieved in high yields (95%) after 72 h at 50 degrees C in a CALB-catalyzed reaction that contained 100 IU enzyme activity, 50 mM DOD, and 100 mM N-methylethanol amine in isoamyl alcohol. The new fatty amide D2AM displayed potent antimicrobial activity towards Gram-positive (Bacillus subtilis and Staphylococcus aureus) and Gram-negative bacteria (Proteus vulgaris and Klebsiella pneumonae). D2AM also exhibited antioxidative activity by its alpha,alpha-diphenyl-beta-picryl-hydrazyl (DPPH) radicals scavenging effects. Title: Neuroprotective effect of carvedilol, an adrenergic antagonist against colchicine induced cognitive impairment and oxidative damage in rat Kumar A, Dogra S Ref: Pharmacol Biochem Behav, 92:25, 2009 : PubMed ESTHER: Kumar_2009_Pharmacol.Biochem.Behav_92_25 PubMedSearch: Kumar 2009 Pharmacol.Biochem.Behav 92 25 PubMedID: 18992766 Abstract Cognitive impairment and weak intellectual capacity is a gradually progressive neurodegenerative problem. Growing evidences indicate that oxidants and antioxidant defenses interact in a vicious cycle, which plays a critical role in the pathogenesis of cognitive dysfunction. The present study was carried out to elucidate the neuroprotective effect of carvedilol against the colchicine-induced cognitive impairment and oxidative damage in rats. Colchicine (15 microg/5 microl), a microtubule disrupting agent when administered intracerebroventricularly in rats resulted in poor memory retention in both Morris water maze, elevated plus maze task paradigms and caused marked oxidative stress as indicated by significant increase in malondialdehyde, nitrite levels, depletion of SOD, catalase, glutathione-S-transferase activity and reduced glutathione levels. It also caused a significant decrease in the acetylcholinesterase activity. Chronic administration of carvedilol (2.5 and 5.0 mg/kg; p.o.) for a period of 25 days, starting 4 days prior to colchicine administration resulted in an improvement in memory retention, attenuation of oxidative damage and restoration of acetylcholinesterase activity. Present study demonstrates a neuroprotective effect of carvedilol against colchicine-induced cognitive impairment and associated oxidative damage. Title: Protective effect of rivastigmine against 3-nitropropionic acid-induced Huntington's disease like symptoms: possible behavioural, biochemical and cellular alterations Kumar P, Kumar A Ref: European Journal of Pharmacology, 615:91, 2009 : PubMed ESTHER: Kumar_2009_Eur.J.Pharmacol_615_91 PubMedSearch: Kumar 2009 Eur.J.Pharmacol 615 91 PubMedID: 19445928 Abstract 3-Nitropropionic acid inhibits succinate dehydrogenase, complex II enzyme in the mitochondrial respiratory chain that leads to cellular energy deficit and oxidative stress. Huntington's disease is characterized by abnormal body movements (chorea) and cognitive dysfunctions. Rivastigmine, a well known cholinesterase inhibitor used in the management of Alzheimer's disease in a clinical practice. Recent clinical studies suggest the potential role of rivastigmine in the management of Huntington's disease. The present study has been designed to explore the possible role of rivastigmine against 3-nitropropionic acid induced behavioral, biochemical and cellular alterations. Intraperitoneal administration of 3-nitropropionic acid (10 mg/kg for 14 days) caused significant loss in body weight, motor in coordination (locomotor activity and rota rod performance) and poor memory retention in Morris water maze and elevated plus maze performance tasks as compared to vehicle treated animals. Biochemical analysis revealed significant increase in lipid peroxidation, nitrite concentration and depleted superoxide dismutase, catalase levels and alterations in mitochondrial complex enzymes (I, II, IV and MTT assay) in the different regions (striatum, cortex and hippocampus) of rat brain. Rivastigmine (0.5, 1 and 2 mg/kg, orally) once daily treatment for a period of 14 days significantly improved motor performance and cognitive task in both Morris water maze and elevated plus maze tests. Further, rivastigmine treatment significantly attenuated oxidative damage and improved mitochondrial complexes enzyme activities in different regions (striatum, cortex and hippocampus) of rat brain. The results show that rivastigmine could be used as an effective therapeutic agent in the management of Huntington's disease and related conditions. Title: Protective role of sertraline against 3-nitropropionic acid-induced cognitive dysfunction and redox ratio in striatum, cortex and hippocampus of rat brain Kumar P, Kumar A Ref: Indian J Exp Biol, 47:715, 2009 : PubMed ESTHER: Kumar_2009_Indian.J.Exp.Biol_47_715 PubMedSearch: Kumar 2009 Indian.J.Exp.Biol 47 715 PubMedID: 19957883 Abstract Huntington's disease (HD) is an inherited progressive neurodegenerative disorder in human characterized by progressive loss of movement and cognitive disturbances. 3-nitropropionic acid (3-NP; a mitochondrial toxin) produces age-dependent oxidative linked striatal damage, responsible for HD like symptoms. In the present study protective effect of sertraline in 3-NP induced HD like symptoms was evaluated in rats. Systemic administration of 3-NP (10 mg/kg for 14 days) resulted in impairment of memory as assessed in Morris water maze and elevated plus paradigm tasks. Biochemical analysis revealed that systemic 3-NP administration significantly impaired reduced glutathione, total glutathione, oxidized glutathione and glutathione-S-transferase levels, whereas the level of acetylcholinesterase enzyme increased in striatum, cortex and hippocampus regions of rat brain. Sertraline (5 and 10 mg/kg po) treatment once daily for 14 days significantly improved cognitive performance tasks and glutathione levels in 3-NP treated group. However, combination of yohimbine (2 mg/kg) (non selective serotonin receptors antagonist) with the higher dose of sertraline (10 mg/kg) did not influence the protective action of sertraline. Result shows that neuroprotective and antioxidant like effect of sertraline is independent of its conventional action on 5-HT receptor. Title: Effect of N-acetyl cysteine against aluminium-induced cognitive dysfunction and oxidative damage in rats Prakash A, Kumar A Ref: Basic Clin Pharmacol Toxicol, 105:98, 2009 : PubMed ESTHER: Prakash_2009_Basic.Clin.Pharmacol.Toxicol_105_98 PubMedSearch: Prakash 2009 Basic.Clin.Pharmacol.Toxicol 105 98 PubMedID: 19389043 Abstract Aluminium is a potent neurotoxin involved in the initiation and progression of various cognitive disorders like Alzheimer's disease. Chronic aluminium exposure induces oxidative stress and increases amyloid beta levels in vivo. The role of oxidative stress has been well-suggested in these cognitive problems. Therefore, the present study was designed to explore the possible role of N-acetyl cysteine against aluminium mediating cognitive dysfunction and oxidative stress in rats. Aluminium chloride (100 mg/kg, p.o.) was given to rats daily for 6 weeks. N-acetyl cysteine (per se; 50 and 100 mg/kg, i.p.) pre-treatment was given 30 min. before aluminium daily for 6 weeks. On the third (21st day) and sixth week (42nd day) of the study, various behavioural tests (Morris water maze and elevated plus maze task paradigms) and locomotion (photoactometer) were done to evaluate cognitive tasks. The rats were killed on the 43rd day following the last behavioural test, and various biochemical tests were performed to assess the extent of oxidative damage. Chronic aluminium chloride administration resulted in poor retention of memory in Morris water maze, elevated plus maze task paradigms and caused marked oxidative damage. It also caused a significant increase in the acetylcholinesterase activity. Chronic administration of N-acetyl cysteine significantly improved memory retention in tasks, attenuated oxidative damage and acetylcholinesterase activity in aluminium-treated rats. The study suggests a neuroprotective effect of N-acetyl cysteine against aluminium-induced cognitive dysfunction and oxidative damage. Title: Effect of chronic treatment of carvedilol on oxidative stress in an intracerebroventricular streptozotocin induced model of dementia in rats Prakash AK, Kumar A Ref: J Pharm Pharmacol, 61:1665, 2009 : PubMed ESTHER: Prakash_2009_J.Pharm.Pharmacol_61_1665 PubMedSearch: Prakash 2009 J.Pharm.Pharmacol 61 1665 PubMedID: 19958590 Abstract OBJECTIVES: Oxidative stress is emerging as an important issue in the pathogenesis of dementia. This study was conducted to investigate the possible neuroprotective effects of carvedilol against streptozotocin induced behavioural alterations and oxidative damage in rats. METHODS: An intracerbroventricular cannula was implanted in the lateral ventricles of male Wistar rats. Various behavioural (locomotor activity, Morris water maze task) and biochemical parameters (lipid peroxidation, nitrate concentration, catalase, acetylcholinesterase, reduced glutathione and protein) were assessed. KEY FINDINGS: Intracerebroventricular administration of streptozotocin caused a significant memory deficit as evaluated in the Morris water maze task paradigms, and caused marked oxidative damage as indicated by significant increases in malondialdehyde and nitrite levels, and depletion of superoxide dismutase, catalase and reduced glutathione levels. It also caused a significant increase in acetylcholinesterase activity. Chronic administration of carvedilol (1 and 2 mg/kg, i.p.) for a period of 25 days starting 4 days before streptozotocin administration resulted in an improvement in memory retention, and attenuation of oxidative damage and acetylcholinesterase activity. CONCLUSIONS: This study demonstrates the effectiveness of carvedilol in preventing cognitive deficits as well as the oxidative stress caused by intracerbroventicular administration of streptozotocin in rats. Carvedilol may have potential in the treatment of neurodegenerative diseases. Title: Discovery of (-)-7-methyl-2-exo-[3'-(6-[18F]fluoropyridin-2-yl)-5'-pyridinyl]-7-azabicyclo[2.2 .1]heptane, a radiolabeled antagonist for cerebral nicotinic acetylcholine receptor (alpha4beta2-nAChR) with optimal positron emission tomography imaging properties Gao Y, Kuwabara H, Spivak CE, Xiao Y, Kellar K, Ravert HT, Kumar A, Alexander M, Hilton J and Horti AG <2 more author(s)> Gao Y, Kuwabara H, Spivak CE, Xiao Y, Kellar K, Ravert HT, Kumar A, Alexander M, Hilton J, Wong DF, Dannals RF, Horti AG (- 2) Ref: Journal of Medicinal Chemistry, 51:4751, 2008 : PubMed ESTHER: Gao_2008_J.Med.Chem_51_4751 PubMedSearch: Gao 2008 J.Med.Chem 51 4751 PubMedID: 18605717 Abstract Several isomers of 7-methyl-2-exo-([(18)F]fluoropyridinyl-5'-pyridinyl)-7-azabicyclo[2.2.1]heptane have been developed as radioligands with optimized brain kinetics for PET imaging of nAChR. The binding assay demonstrated that all isomers are beta-nAChR selective ligands with Ki = 0.02-0.3 nM. The experimental lipophilicity values of all isomers were in the optimal range for the cerebral radioligands (log D7.4= 0.67-0.99). The isomers with higher binding affinity manifested slow baboon brain kinetics, whereas the isomer with the lowest binding affinity (Ki = 0.3 nM) ((-)-7-methyl-2- exo-[3'-(6-[(18)F]fluoropyridin-2-yl)-5'-pyridinyl]-7-azabicyclo[2.2.1]heptane, [(18)F](-)-6c) and greatest lipophilicity (log D 7.4 = 0.99) exhibited optimal brain kinetics. [(18)F](-)-6c manifests a unique combination of the optimally rapid brain kinetics, high BP and brain uptake, and favorable metabolic profile. Pharmacological studies showed that (-)-6c is an alpha4beta2-nAChR antagonist with low side effects in mice. This combination of imaging properties suggests that [(18)F]-(-)- 6c is a potentially superior replacement for 2-[(18)F]fluoro-A-85380 and 6-[(18)F]fluoro-A-85380, the only available nAChR PET radioligands for humans. Title: Microsomal epoxide hydrolase (EPHX1), slow (exon 3, 113His) and fast (exon 4, 139Arg) alleles confer susceptibility to squamous cell esophageal cancer Jain M, Tilak AR, Upadhyay R, Kumar A, Mittal B Ref: Toxicol Appl Pharmacol, 230:247, 2008 : PubMed ESTHER: Jain_2008_Toxicol.Appl.Pharmacol_230_247 PubMedSearch: Jain 2008 Toxicol.Appl.Pharmacol 230 247 PubMedID: 18406439 Abstract Genetic polymorphisms in xenobiotic metabolizing enzymes may alter risk of various cancers. Present case-control study evaluated the influence of EPHX1 genetic variations on squamous cell esophageal cancer (ESCC) susceptibility in 107 patients and 320 controls. EPHX1 polymorphic alleles were genotyped by direct sequencing (exon 3, Tyr113His) or PCR-RFLP (exon 4, His139Arg). Patients with exon 3 genotypes (Tyr113His, His113His) and 113His allele were at risk of ESCC (OR(Tyr113His) 2.0, 95% CI=1.2-3.4, p=0.007; OR(His113His) 2.3 95% CI=1.0-5.2, p=0.03 and OR(His) 1.5, 95% CI=1.0-2.1, p=0.01). In contrast, individuals with exon 4, 139Arg allele were at low risk of cancer (OR 0.34, 95% CI=0.20-0.56, p=0.001). However, none of haplotype combinations of exon 3 (Tyr113His) and exon 4 (His139Arg) polymorphisms showed modulation of risk for ESCC. Sub-grouping of patients based on anatomical location of tumor predicted that patients with exon 3, His113His and Tyr113His genotypes were at higher risk for developing ESCC tumor at upper and middle third locations (OR 4.4, 95% CI=1.0-18.5, p=0.04; OR 2.5, 95% CI=1.3-5.0, p=0.005 respectively). The frequency of exon 4, His139Arg genotype was significantly lower in ESCC patients with lower third tumor location as compared to controls (14.8% vs. 36.3%, p=0.02). In case-only study, gene-environment interaction of EPHX1 genotypes with tobacco, alcohol and occupational exposures did not appear to modulate the cancer susceptibility. In conclusion, exon 3, Tyr113His genotype was associated with higher risk of ESCC particularly at upper and middle-third anatomical locations of tumor. However, His139Arg genotype of exon 4, exhibited low risk for ESCC as well as its clinical characteristics. Title: Possible mechanism involved in sleep deprivation-induced memory dysfunction Kalonia H, Bishnoi M, Kumar A Ref: Methods Find Exp Clin Pharmacol, 30:529, 2008 : PubMed ESTHER: Kalonia_2008_Methods.Find.Exp.Clin.Pharmacol_30_529 PubMedSearch: Kalonia 2008 Methods.Find.Exp.Clin.Pharmacol 30 529 PubMedID: 18985181 Abstract Sleep deprivation disrupts various vital biological and metabolic processes that are necessary for health. The present study was designed to investigate the possible mechanisms of sleep deprivation-induced memory dysfunction by using different behavioral, biochemical and neurochemical parameters. Male Wistar rats were sleep deprived for 72 h using a grid suspended over water. Elevated plus maze, passive avoidance and Morris water maze tests were used to assess memory retention in 72-h sleep-deprived animals. Various electrophysiological (sleep-wake cycle), biochemical (lipid peroxidation, reduced glutathione, nitrite, catalase, acetylcholinesterase) and neurochemical parameters (norepinephrine, dopamine and serotonin) were also assessed. Sleep deprivation resulted in memory dysfunction in all the behavioral paradigms, alteration in the sleep-wake cycle (delayed sleep latency, shortening of rapid eye movement [REM] and non-REM [NREM] sleep and increased waking period) and oxidative stress (increased lipid peroxidation and nitrite levels, depletion of reduced glutathione and catalase activity). In addition, increased levels of acetylcholinesterase (AChE; the enzyme responsible for the degradation of acetylcholine) and reduction in norepinephrine and dopamine levels were seen in 72-h sleep-deprived animals. In conclusion, sleep deprivation-induced memory deficits may possibly be due to the combined effect of oxidative damage and alterations in neurotransmitter levels. Title: Heme oxygenase-1-derived carbon monoxide induces the Mycobacterium tuberculosis dormancy regulon Kumar A, Deshane JS, Crossman DK, Bolisetty S, Yan BS, Kramnik I, Agarwal A, Steyn AJ Ref: Journal of Biological Chemistry, 283:18032, 2008 : PubMed ESTHER: Kumar_2008_J.Biol.Chem_283_18032 PubMedSearch: Kumar 2008 J.Biol.Chem 283 18032 PubMedID: 18400743 Gene_locus related to this paper: myctu-RV2627C, myctu-y0571 Abstract The mechanisms that allow Mycobacterium tuberculosis (Mtb) to persist in human tissue for decades and to then abruptly cause disease are not clearly understood. Regulatory elements thought to assist Mtb to enter such a state include the heme two-component sensor kinases DosS and DosT and the cognate response regulator DosR. We have demonstrated previously that O(2), nitric oxide (NO), and carbon monoxide (CO) are regulatory ligands of DosS and DosT. Here, we show that in addition to O(2) and NO, CO induces the complete Mtb dormancy (Dos) regulon. Notably, we demonstrate that CO is primarily sensed through DosS to induce the Dos regulon, whereas DosT plays a less prominent role. We also show that Mtb infection of macrophage cells significantly increases the expression, protein levels, and enzymatic activity of heme oxygenase-1 (HO-1, the enzyme that produces CO), in an NO-independent manner. Furthermore, exploiting HO-1(+/+) and HO-1(-/-) bone marrow-derived macrophages, we demonstrate that physiologically relevant levels of CO induce the Dos regulon. Finally, we demonstrate that increased HO-1 mRNA and protein levels are produced in the lungs of Mtb-infected mice. Our data suggest that during infection, O(2), NO, and CO are being sensed concurrently rather than independently via DosS and DosT. We conclude that CO, a previously unrecognized host factor, is a physiologically relevant Mtb signal capable of inducing the Dos regulon, which introduces a new paradigm for understanding the molecular basis of Mtb persistence. Title: Protective effect of quercetin against ICV colchicine-induced cognitive dysfunctions and oxidative damage in rats Kumar A, Sehgal N, Kumar P, Padi SS, Naidu PS Ref: Phytother Res, 22:1563, 2008 : PubMed ESTHER: Kumar_2008_Phytother.Res_22_1563 PubMedSearch: Kumar 2008 Phytother.Res 22 1563 PubMedID: 18980205 Abstract Intracerebroventricular (i.c.v.) administration of colchicine, a microtubule-disrupting agent, causes cognitive dysfunction and oxidative stress. The present study was designed to investigate the protective effects of quercetin against colchicine-induced memory impairment and oxidative damage in rats. An i.c.v. cannula was implanted in the lateral ventricle of male Wistar rats. Colchicine was administered at dose of 15 microg/rat. Morris water maze and plus-maze performance tests were used to assess memory tasks. Various biochemical parameters such as lipid peroxidation, reduced glutathione, nitrite level, acetylcholinesterase and proteins were also assessed. Central administration of colchicine (15 microg/rat) showed poor retention of memory. Chronic treatment with quercetin (20 and 40 mg/kg, p.o.) twice daily for a period of 25 days beginning 4 days prior to colchicine injection significantly improved the colchicine-induced cognitive impairment. Biochemical analysis revealed that i.c.v. colchicine injection significantly increased lipid peroxidation, nitrite and depleted reduced glutathione activity in the brains of rats. Chronic administration of quercetin significantly attenuated elevated lipid peroxidation and restored the depleted reduced glutathione, acetylcholinesterase activity and nitrite activity. The results of the present study clearly indicated that quercetin has a neuroprotective effect against colchicine-induced cognitive dysfunctions and oxidative damage. This article was published online on 3 November 2008. An error was subsequently identified. This notice is included in the online and print version to indicate that both have been corrected. Title: Effect of curcumin on intracerebroventricular colchicine-induced cognitive impairment and oxidative stress in rats Kumar A, Naidu PS, Seghal N, Padi SS Ref: J Med Food, 10:486, 2007 : PubMed ESTHER: Kumar_2007_J.Med.Food_10_486 PubMedSearch: Kumar 2007 J.Med.Food 10 486 PubMedID: 17887943 Abstract This study was designed to investigate the protective effects of curcumin against colchicine-induced cognitive impairment and oxidative stress in rats. Male Wistar rats (weighing 150-200 g) received colchicine intracerebroventricularly (15 microg per rat), and cognitive dysfunctions were evaluated by the Morris water maze and the plus maze performance task and supported by biochemical tests. Central administration of colchicine caused memory deficit in both the Morris water maze and the elevated plus maze task paradigm tasks. Chronic treatment with curcumin (5-50 mg/kg, p.o.) twice daily for a period of 25 days beginning 4 days prior to colchicine injection significantly improved the colchicine-induced cognitive impairment. Biochemically, chronic administration of curcumin significantly reduced the elevated lipid peroxidation, restored the decreased reduced glutathione level and acetylcholinesterase activity, and attenuated the raised colchicine-induced elevated nitrite levels. The results of the present study indicate that curcumin has a protective role against colchicine-induced cognitive impairment and associated oxidative stress. Title: Colchicines-induced neurotoxicity as an animal model of sporadic dementia of Alzheimer's type Kumar A, Seghal N, Naidu PS, Padi SS, Goyal R Ref: Pharmacol Rep, 59:274, 2007 : PubMed ESTHER: Kumar_2007_Pharmacol.Rep_59_274 PubMedSearch: Kumar 2007 Pharmacol.Rep 59 274 PubMedID: 17652827 Abstract Alzheimer's disease (AD) is the most common type of dementia disorder of elderly affecting millions of people. The pathophysiology of the disease is complex and involves multiple pathways of neuronal damage. Sporadic dementia of Alzheimer's type (SDAT) has been shown to be associated with microtubular dysfunction and is characterized by the appearance of specific cytoskeletal cellular abnormalities, including neurofibrillary tangles and senile plaques. Intracerebroventricular (i.c.v) administration of colchicine, a microtubule-disrupting agent, causes cognitive dysfunction as evidenced by poor retention of memory in both Morris water maze and elevated plus-maze task paradigms that is associated with excessive free radical generation. Biochemical analysis revealed that icv colchicine injection significantly induced lipid peroxidation, increased nitrite and depleted reduced glutathione (GSH) and acetylcholinesterase (AChE) level in rat brains. Chronic treatment with rivastigmine (0.625 and 2.5 mg/kg, po) twice daily for a period of 25 days beginning 4 days prior to colchicine injection significantly improved the colchicine-induced cognitive impairment and reduced AChE level. The results of the present study clearly indicated that colchicines-induced cognitive impairment and oxidative stress in animals and can be used as an animal model for drug screening for Alzheimer's disease. Title: Role of combined administration of Tiron and glutathione against aluminum-induced oxidative stress in rat brain Sharma P, Ahmad Shah Z, Kumar A, Islam F, Mishra KP Ref: J Trace Elem Med Biol, 21:63, 2007 : PubMed ESTHER: Sharma_2007_J.Trace.Elem.Med.Biol_21_63 PubMedSearch: Sharma 2007 J.Trace.Elem.Med.Biol 21 63 PubMedID: 17317527 Abstract The current study was carried out to investigate the potential role of 4,5 dihydroxy benzene 1,3 disulfonic acid di sodium salt (Tiron) and glutathione (GSH) either individually or in combination against aluminum (Al)-induced toxicity in Wistar rats. Animals were exposed to aluminum chloride at a dose of 172.5mg/kg/d orally for 10 weeks. Tiron and GSH were administered at a dose of 471-mg/kg/d i.p. and 100mg/kg/d orally, respectively, for 7 consecutive days. Tiron is a diphenolic chelating compound which forms water soluble complexes with a large number of metal ions. Induction of oxidative stress was recorded in brain and serum after Al exposure. Significant decrease was recorded in reduced glutathione (GSH), glutathione reductase (GR), glutathione peroxidase (GP(x)), catalase (CAT), superoxide dismutase (SOD), acetyl cholinesterase (AChE) and an increase was observed in thiobarbituric acid reacting substance (TBARS) and glutathione-S-transferase (GST) in brain and serum. Most of the above parameters responded positively to individual therapy with Tiron, but more pronounced beneficial effects on the above-described parameters were observed when Tiron was administered in combination with GSH. Inductively Coupled Plasma-Atomic Emission Spectroscopy (ICP-AES) studies also showed significantly high concentration of Al in brain and blood. Tiron was slightly more effective then GSH in reducing the concentration of Al from the brain and blood, however, no further improvement was recorded when Tiron was administered in combination with GSH in reducing the concentration of Al. Title: Selective loss of lin genes from hexachlorocyclohexane-degrading Pseudomonas aeruginosa ITRC-5 under different growth conditions Singh AK, Chaudhary P, Macwan AS, Diwedi UN, Kumar A Ref: Applied Microbiology & Biotechnology, 76:895, 2007 : PubMed ESTHER: Singh_2007_Appl.Microbiol.Biotechnol_76_895 PubMedSearch: Singh 2007 Appl.Microbiol.Biotechnol 76 895 PubMedID: 17602219 Gene_locus related to this paper: sphpi-linb Abstract The chlorinated insecticide gamma-hexachlorocyclohexane (gamma-HCH) is sequentially metabolized by the products of linA, linB, linC, linD, linE, and linF genes to beta-ketoadipate, which is subsequently mineralized. Two or more copies of these genes are present in the bacterium Pseudomonas aeruginosa ITRC-5 that was isolated earlier by selective enrichment on technical-HCH. At least one copy of linA, linB, linC, linD, and possibly linE is lost from ITRC-5 upon its growth on gamma-HCH. All the lin genes, however, are lost when the bacterium was grown in Luria-Bertani (LB) medium. The loss of lin genes is accompanied with the loss/rearrangement of insertion sequence IS6100 genes. Concomitant to the loss of lin genes, the degradation of HCH-isomers by "gamma-HCH grown cells" is slower, when compared with "technical-HCH grown cells", and is completely lost by "LB-grown cells". The selective loss of lin genes during different growth conditions has not been reported before and is expected to help in understanding the dynamism of degradative genes. Title: Crystal structure of homoserine O-succinyltransferase from Bacillus cereus at 2.4 A resolution Zubieta C, Krishna SS, McMullan D, Miller MD, Abdubek P, Agarwalla S, Ambing E, Astakhova T, Axelrod HL and Wilson IA <33 more author(s)> Zubieta C, Krishna SS, McMullan D, Miller MD, Abdubek P, Agarwalla S, Ambing E, Astakhova T, Axelrod HL, Carlton D, Chiu HJ, Clayton T, Deller M, DiDonato M, Duan L, Elsliger MA, Grzechnik SK, Hale J, Hampton E, Han GW, Haugen J, Jaroszewski L, Jin KK, Klock HE, Knuth MW, Koesema E, Kumar A, Marciano D, Morse AT, Nigoghossian E, Oommachen S, Reyes R, Rife CL, van den Bedem H, Weekes D, White A, Xu Q, Hodgson KO, Wooley J, Deacon AM, Godzik A, Lesley SA, Wilson IA (- 33) Ref: Proteins, 68:999, 2007 : PubMed ESTHER: Zubieta_2007_Proteins_68_999 PubMedSearch: Zubieta 2007 Proteins 68 999 PubMedID: 17546672 Gene_locus related to this paper: bacce-BC4730 Title: Differential effects of cyclooxygenase inhibitors on intracerebroventricular colchicine-induced dysfunction and oxidative stress in rats Kumar A, Seghal N, Padi SV, Naidu PS Ref: European Journal of Pharmacology, 551:58, 2006 : PubMed ESTHER: Kumar_2006_Eur.J.Pharmacol_551_58 PubMedSearch: Kumar 2006 Eur.J.Pharmacol 551 58 PubMedID: 17027965 Abstract Alzheimer's disease is a progressive neurological and psychiatric disorder. Oxidative stress and neuroinflammation have been implicated in pathophysiology of Alzheimer's disease. Inflammatory cells, such as astrocytes and microglia, are activated in areas of the brain affected by amyloid plaques and inflammatory mediators including cytokines, chemokines, prostaglandins, oxygen free radicals and reactive nitrogen species may have a crucial role in Alzheimer's disease pathogenesis. Central administration of colchicine, a microtubule-disrupting agent, causes loss of cholinergic neurons and cognitive dysfunction that is associated with excessive free radical generation. The present study was aimed to evaluate the effects of cyclooxygenase inhibitors against colchicine-induced cognitive dysfunction and oxidative stress in rats. Following intracerebroventricular (i.c.v.) administration of colchicine (15 microg/5 microl), rats exhibited poor retention of memory in Morris water maze and elevated plus maze task paradigms and oxidative stress in rats. Chronic treatment with naproxen (per se; 20 and 40 mg/kg, p.o.) or valdecoxib (per se; 5 and 10 mg/kg, p.o.) daily respectively for a period of 25 days beginning 4 days prior to colchicine injection significantly improved colchicine-induced cognitive impairment. Intracerebroventricular colchicine injection resulted in free radical generation characterized by alterations in oxidative stress markers with a significant increase in malondialdehyde and nitrite levels and depletion of reduced glutathione levels in the brains of rats. It also caused a decrease in acetylcholinesterase activity. Besides, improving cognitive dysfunction, chronic administration of cyclooxygenase inhibitors (naproxen and valdecoxib) significantly reduced elevated malondialdehyde, nitrite levels and restored reduced glutathione levels and acetylcholinesterase activity. The results of the present study indicated that naproxen (per se; 20 and 40 mg/kg, p.o.) or valdecoxib (per se; 5 and 10 mg/kg, p.o.) treatment has a neuroprotective role against colchicine-induced cognitive impairment and associated oxidative stress. The present findings further support the potential use of cyclooxygenase inhibitors in treatment of neurodegenerative diseases such as Alzheimer's disease. Title: Cocrystallization of random copolymers of omega-pentadecalactone and epsilon-caprolactone synthesized by lipase catalysis Ceccorulli G, Scandola M, Kumar A, Kalra B, Gross RA Ref: Biomacromolecules, 6:902, 2005 : PubMed ESTHER: Ceccorulli_2005_Biomacromolecules_6_902 PubMedSearch: Ceccorulli 2005 Biomacromolecules 6 902 PubMedID: 15762658 Gene_locus related to this paper: canar-LipB Abstract Random copolymers were prepared by Candida antarctica lipase B (Novozyme-435) catalyzed copolymerization of omega-pentadecalactone (PDL) with epsilon-caprolactone (CL). Over the whole composition range PDL-CL copolymers are highly crystalline (melting enthalpy by differential scanning calorimetry, above 100 J/g; crystallinity degree by wide-angle X-ray scattering, WAXS, 60-70%). The copolymers melt at temperatures that linearly decrease with composition from that of poly(omega-pentadecalactone) (PPDL; 97 degrees C) to that of poly(epsilon-caprolactone) (PCL; 59 degrees C). The WAXS profiles of PCL and PPDL homopolymers are very similar, except for the presence in PPDL of the (001) reflection at 2theta = 4.58 degrees that corresponds to a 19.3 angstroms periodicity in the chain direction. In PDL-CL copolymers the intensity of this reflection decreases with increasing content of CL units and vanishes at 50 mol % CL, as a result of randomization of the ester group alignment and loss of chain periodicity. PDL-CL copolymers crystallize in a lattice that gradually changes from that of one homopolymer to that of the other, owing to comonomer isomorphous substitution. Cocrystallization of comonomer units is also shown by a random PDL-CL copolymer obtained in a polymerization/transesterification reaction catalyzed by C. antarctica lipase B (Novozyme-435) starting from preformed PCL and PDL monomer. Title: Degradation of beta-Hexachlorocyclohexane by Haloalkane Dehalogenase LinB from Sphingomonas paucimobilis UT26 Nagata Y, Prokop Z, Sato Y, Jerabek P, Kumar A, Ohtsubo Y, Tsuda M, Damborsky J Ref: Applied Environmental Microbiology, 71:2183, 2005 : PubMed ESTHER: Nagata_2005_Appl.Environ.Microbiol_71_2183 PubMedSearch: Nagata 2005 Appl.Environ.Microbiol 71 2183 PubMedID: 15812056 Abstract Beta-Hexachlorocyclohexane (beta-HCH) is the most recalcitrant among the alpha-, beta-, gamma-, and delta-isomers of HCH and causes serious environmental pollution problems. We demonstrate here that the haloalkane dehalogenase LinB, reported earlier to mediate the second step in the degradation of gamma-HCH in Sphingomonas paucimobilis UT26, metabolizes beta-HCH to produce 2,3,4,5,6-pentachlorocyclohexanol. Title: Role of piperonyl butoxide in the toxicity of chlorpyrifos to Ceriodaphnia dubia and Xenopus laevis El-Merhibi A, Kumar A, Smeaton T Ref: Ecotoxicology & Environmental Safety, 57:202, 2004 : PubMed ESTHER: El-Merhibi_2004_Ecotoxicol.Environ.Saf_57_202 PubMedSearch: El-Merhibi 2004 Ecotoxicol.Environ.Saf 57 202 PubMedID: 14759667 Inhibitor(s) related to this paper: Piperonyl-butoxide Abstract The use of chemical inhibitors/inducers is one of the strategies employed to determine whether a particular metabolic pathway is involved in the metabolism of a xenobiotic. The objective of this study was to assess the role of piperonyl butoxide (PBO) on the toxicity of an organophosphorus insecticide, chlorpyrifos (CPF) to two species, Ceriodaphnia dubia (waterflea) and Xenopus laevis (South African clawed frog). Chlorpyrifos was highly toxic to C. dubia (48-h LC50: 0.05 microg/L) in comparison with X. laevis (96-h LC50: 2410 microg/L). Piperonyl butoxide at 200 microg/L reduced the toxicity of chlorpyrifos to C. dubia by a factor of 6. Piperonyl butoxide at 3000 microg/L also reduced the toxicity of CPF to X. laevis with respect to mortality and malformations. Acetylcholinesterase (AChE) activity was used as a biomarker to further assess the role of PBO in chlorpyrifos toxicity. X. laevis exposed to CPF and PBO exhibited a biphasic response in terms of AChE activity with an initial increase in the AChE activity followed by a drastic decrease. The results from the present study indicate that C. dubia and X. laevis have the capability to metabolize chlorpyrifos via cytochromes P450 mediated reactions. The results also indicate that the use of the biomarker AChE is useful in determining metabolic processes of organophosphorus insecticides, which require metabolic activation. Title: Imprinted mesodermal specific transcript (MEST) and H19 genes in renal development and diabetes Kanwar YS, Pan X, Lin S, Kumar A, Wada J, Haas CS, Liau G, Lomasney JW Ref: Kidney Int, 63:1658, 2003 : PubMed ESTHER: Kanwar_2003_Kidney.Int_63_1658 PubMedSearch: Kanwar 2003 Kidney.Int 63 1658 PubMedID: 12675841 Abstract BACKGROUND: Imprinted genes, mesodermal specific cDNA or transcript (MEST) and H19, are implicated in peri-implantation embryogenesis, and their expression was assessed in embryonic kidneys undergoing glucose-induced dysmorphogenesis. METHODS: MEST and H19 mRNA expression was assessed by Northern blot analysis in embryonic kidneys of mice harvested at day 15 to day 19 of gestation and of 1-week-old mice obtained from hyperglycemic mothers. A full-length mouse MEST cDNA was isolated, subcloned into an expression vector, a recombinant protein prepared and an antibody raised; the latter was used to assess protein expression by immunoprecipitation and immunofluorescence microscopy in day 13 metanephric explants subjected to high glucose ambience. Also, MEST mRNA expression was assessed in high d glucose-treated explants by competitive reverse transcription-polymerase chain reaction (RT-PCR) analyses and by in situ tissue autoradiography. RESULTS: A high expression of MEST and H19 with respective transcript size of approximately 2.7 and approximately 2.4 kb was observed in fetal kidneys, and their expression decreased during the successive stages of gestation and was undetectable in the postnatal period. At day 13, the MEST mRNA was expressed in the mesenchyme, while H19 was expressed in the ureteric bud branches and epithelial elements of the metanephros. Their expression decreased with progression of gestation. By competitive RT-PCR and Northern blot and in situ autoradiographic analyses, both MEST and H19 expressions decreased in day 13 explants treated with high glucose and in the kidneys of fetuses obtained from diabetic mothers. The MEST protein expression was observed in the metanephric epithelial elements and ureteric bud branches instead of in the mesenchyme, and its expression decreased in glucose-treated dysmorphogenetic explants, as assessed by immunofluorescence and immunoprecipitation methods. CONCLUSION: MEST and H19 imprinted genes are strategically located in the mammalian embryonic metanephros. They are developmentally regulated and their concomitant decreased expression in high glucose ambience or diabetic state did not follow the prevailing dogma of reciprocal inactivation/activation of imprinted genes, and such a decrease may be responsible for the perturbed epithelial:mesenchymal interactions leading to dysmorphogenesis of the mammalian metanephros. Title: Identification of developmentally regulated mesodermal-specific transcript in mouse embryonic metanephros Kanwar YS, Kumar A, Ota K, Lin S, Wada J, Chugh S, Wallner EI Ref: American Journal of Physiology Renal Physiol, 282:F953, 2002 : PubMed ESTHER: Kanwar_2002_Am.J.Physiol.Renal.Physiol_282_F953 PubMedSearch: Kanwar 2002 Am.J.Physiol.Renal.Physiol 282 F953 PubMedID: 11934706 Abstract Mesodermal-specific cDNA or transcript (MEST) was identified by suppression subtractive hybridization-PCR of cDNA isolated from embryonic day 13 vs. newborn mice kidneys. At day 13 of mouse gestation, a high expression of MEST, with a single approximately 2.7-kb transcript that was exclusively localized to the metanephric mesenchyme was observed. The MEST mRNA expression gradually decreased during the later stages and then abruptly decreased in the newborn kidneys and subsequent postnatal life, after which a very mild expression persisted in the glomerular mesangium. Regression in mRNA expression during embryonic renal development appears to be related to methylation of the MEST gene. Treatment of metanephroi, harvested at day 13 of gestation with MEST-specific antisense oligodeoxynucleotide resulted in a dose-dependent decrease in the size of the explants and the nephron population. This was associated with a selective decrease in MEST mRNA expression and accelerated apoptosis of the mesenchyme. These findings suggest that MEST, a gene with a putative mesenchymal cell-derived protein, conceivably plays a role in mammalian metanephric development. Title: Subcellular localization of the yeast proteome Kumar A, Agarwal S, Heyman JA, Matson S, Heidtman M, Piccirillo S, Umansky L, Drawid A, Jansen R and Snyder M <5 more author(s)> Kumar A, Agarwal S, Heyman JA, Matson S, Heidtman M, Piccirillo S, Umansky L, Drawid A, Jansen R, Liu Y, Cheung KH, Miller P, Gerstein M, Roeder GS, Snyder M (- 5) Ref: Genes Dev, 16:707, 2002 : PubMed ESTHER: Kumar_2002_Genes.Dev_16_707 PubMedSearch: Kumar 2002 Genes.Dev 16 707 PubMedID: 11914276 Gene_locus related to this paper: yeast-mgll Abstract Protein localization data are a valuable information resource helpful in elucidating eukaryotic protein function. Here, we report the first proteome-scale analysis of protein localization within any eukaryote. Using directed topoisomerase I-mediated cloning strategies and genome-wide transposon mutagenesis, we have epitope-tagged 60% of the Saccharomyces cerevisiae proteome. By high-throughput immunolocalization of tagged gene products, we have determined the subcellular localization of 2744 yeast proteins. Extrapolating these data through a computational algorithm employing Bayesian formalism, we define the yeast localizome (the subcellular distribution of all 6100 yeast proteins). We estimate the yeast proteome to encompass approximately 5100 soluble proteins and >1000 transmembrane proteins. Our results indicate that 47% of yeast proteins are cytoplasmic, 13% mitochondrial, 13% exocytic (including proteins of the endoplasmic reticulum and secretory vesicles), and 27% nuclear/nucleolar. A subset of nuclear proteins was further analyzed by immunolocalization using surface-spread preparations of meiotic chromosomes. Of these proteins, 38% were found associated with chromosomal DNA. As determined from phenotypic analyses of nuclear proteins, 34% are essential for spore viability--a percentage nearly twice as great as that observed for the proteome as a whole. In total, this study presents experimentally derived localization data for 955 proteins of previously unknown function: nearly half of all functionally uncharacterized proteins in yeast. To facilitate access to these data, we provide a searchable database featuring 2900 fluorescent micrographs at http:\/\/ygac.med.yale.edu. Title: Acute toxicity of mixtures of chlorpyrifos, profenofos, and endosulfan to Ceriodaphnia dubia Woods M, Kumar A, Correll R Ref: Bulletin of Environmental Contamination & Toxicology, 68:801, 2002 : PubMed ESTHER: Woods_2002_Bull.Environ.Contam.Toxicol_68_801 PubMedSearch: Woods 2002 Bull.Environ.Contam.Toxicol 68 801 PubMedID: 12012054 Title: Profenofos residues in wild fish from cotton-growing areas of New South Wales, Australia Kumar A, Chapman JC Ref: J Environ Qual, 30:740, 2001 : PubMed ESTHER: Kumar_2001_J.Environ.Qual_30_740 PubMedSearch: Kumar 2001 J.Environ.Qual 30 740 PubMedID: 11401263 Abstract The organophosphorus (OP) pesticide profenofos (O-4-bromo-2-chlorophenyl O-ethyl S-propyl phosphorothioate) is used heavily in cotton-growing areas of eastern Australia toward the end of the growing season. European carp (Cyprinus carpio), bony bream (Nematalosa erebi), and mosquitofish (Gambusia holbrooki) were collected from the cotton-growing areas around Wee Waa, New South Wales, to determine the relationship between profenofos residues and acetyl-cholinesterase (AChE) activity in wild fish. Profenofos concentrations in water, sediment, and fish tissue reflected its general level of use; levels in March 1994 were significantly higher than in 1993 and generally decreased in May, 6 wk after cessation of spraying. Residues in carp and bony bream generally correlated with concentrations in water and sediment, although residues in fish tend to persist longer at some sites. Acetylcholinesterase inhibition was a useful indicator of profenofos exposure within a season, particularly if linked with residue measurements. Bony bream and gravid female mosquitofish recovered AChE levels more slowly than carp or nongravid mosquitofish. Recovery in creeks was generally more rapid than in lagoons. Title: Poly(3-hydroxybutyrate)-depolymerase from Pseudomonas lemoignei: catalysis of esterifications in organic media Kumar A, Gross RA, Jendrossek D Ref: J Org Chem, 65:7800, 2000 : PubMed ESTHER: Kumar_2000_J.Org.Chem_65_7800 PubMedSearch: Kumar 2000 J.Org.Chem 65 7800 PubMedID: 11073584 Abstract Lipase catalysis in nonaqueous media is recognized as a powerful tool in organic and more recently polymer synthesis. Even though none of the currently known polyhydroxyalkanoate (PHA) depolymerases have lipase activity, they do have a catalytic center that resembles that of lipases. Motivated by the above, the potential of using the poly(3-hydroxybutyrate), PHB, depolymerase from Psuedomonas lemoignei in organic media to catalyze ester-forming reactions was investigated. The effect of different organic solvents (benzene-d(6), cyclohexane-d(12), and acetonitrile-d(3)) on the activity of the PHB-depolymerase toward propylation of L-lactide was studied. A significant difference in the catalytic rate was observed as a function of solvent polarity. The selectivity of the PHB-depolymerase (P. lemoignei) to catalyze the propylation of a series of different lactones including epsilon-caprolactone, delta-butyrolactone, gamma-butyrolactone, and D, L, meso, and racemic lactides has been studied with the PHB-depolymerase (P. lemoignei) in organic solvents. Important differences in the reactivity of these lactones, as well as selective hydrolysis of stereochemically different linear lactic acid dimers, were observed. Moreover, the ability of the PHB-depolymerase to catalyze the solventless polymerization of epsilon-caprolactone and trimethylene carbonate was investigated. Title: Candida antartica lipase B catalyzed polycaprolactone synthesis: effects of organic media and temperature Kumar A, Gross RA Ref: Biomacromolecules, 1:133, 2000 : PubMed ESTHER: Kumar_2000_Biomacromolecules_1_133 PubMedSearch: Kumar 2000 Biomacromolecules 1 133 PubMedID: 11709835 Abstract Engineering of the reaction medium and study of an expanded range of reaction temperatures were carried out in an effort to positively influence the outcome of Novozyme-435 (immobilized Lipase B from Candida antarctica) catalyzed epsilon-CL polymerizations. A series of solvents including acetonitrile, dioxane, tetrahydrofuran, chloroform, butyl ether, isopropyl ether, isooctane, and toluene (log P from -1.1 to 4.5) were evaluated at 70 degrees C. Statistically (ANOVA), two significant regions were observed. Solvents having log P values from -1.1 to 0.49 showed low propagation rates (< or = 30% epsilon-CL conversion in 4 h) and gave products of short chain length (Mn < or = 5200 g/mol). In contrast, solvents with log P values from 1.9 to 4.5 showed enhanced propagation rates and afforded polymers of higher molecular weight (Mn = 11,500-17,000 g/mol). Toluene, a preferred solvent for this work, was studied at epsilon-CL to toluene (wt/vol) ratios from 1:1 to 10:1. The ratio 1:2 was selected since, for polymerizations at 70 degrees C, 0.3 mL of epsilon-CL and 4 h, gave high monomer conversions and Mn values (approximately 85% and approximately 17,000 g/mol, respectively). Increasing the scale of the reaction from 0.3 to 10 mL of CL resulted in a similar isolated product yield, but the Mn increased from 17,200 to 44,800 g/mol. Toluene appeared to help stabilize Novozyme-435 so that lipase-catalyzed polymerizations could be conducted effectively at 90 degrees C. For example, within only 2 h at 90 degrees C (toluene-d8 to epsilon-CL, 5:1, approximately 1% protein), the % monomer conversion reached approximately 90%. Also, the controlled character of these polymerizations as a function of reaction temperature was evaluated. Title: Systemic administration of defined extracts from Withania somnifera (Indian Ginseng) and Shilajit differentially affects cholinergic but not glutamatergic and GABAergic markers in rat brain Schliebs R, Liebmann A, Bhattacharya SK, Kumar A, Ghosal S, Bigl V Ref: Neurochem Int, 30:181, 1997 : PubMed ESTHER: Schliebs_1997_Neurochem.Int_30_181 PubMedSearch: Schliebs 1997 Neurochem.Int 30 181 PubMedID: 9017665 Abstract Although some promising results have been achieved by acetylcholinesterase inhibitors, an effective therapeutic intervention in Alzheimer's disease still remains an important goal. Sitoindosides VII-X, and withaferin-A, isolated from aqueous methanol extract from the roots of cultivated varieties of Withania somnifera (known as Indian Ginseng), as well as Shilajit, a pale-brown to blackish brown exudation from steep rocks of the Himalaya mountain, are used in Indian medicine to attenuate cerebral functional deficits, including amnesia, in geriatric patients. The present investigation was conducted to assess whether the memory-enhancing effects of plant extracts from Withania somnifera and Shilajit are owing to neurochemical alterations of specific transmitter systems. Therefore, histochemistry to analyse acetylcholinesterase activity as well as receptor autoradiography to detect cholinergic, glutamatergic and GABAergic receptor subtypes were performed in brain slices from adult male Wistar rats, injected intraperitoneally daily with an equimolar mixture of sitoindosides VII-X and withaferin-A (prepared from Withania somnifera) or with Shilajit, at doses of 40 mg/kg of body weight for 7 days. Administration of Shilajit led to reduced acetylcholinesterase staining, restricted to the basal forebrain nuclei including medial septum and the vertical limb of the diagonal band. Systemic application of the defined extract from Withania somnifera, however, led to differential effects on AChE activity in basal forebrain nuclei: slightly enhanced AChE activity was found in the lateral septum and globus pallidus, whereas in the vertical diagonal band AChE activity was reduced following treatment with sitoindosides VII-X and withaferin-A. These changes were accompanied by enhanced M1-muscarinic cholinergic receptor binding in lateral and medial septum as well as in frontal cortices, whereas the M2-muscarinic receptor binding sites were increased in a number of cortical regions including cingulate, frontal, piriform, parietal and retrosplenial cortex. Treatment with Shilajit or the defined extract from Withania somnifera affected neither GABAA and benzodiazepine receptor binding nor NMDA and AMPA glutamate receptor subtypes in any of the cortical or subcortical regions studied. The data suggest that Shilajit and the defined extract from Withania somnifera affect preferentially events in the cortical and basal forebrain cholinergic signal transduction cascade. The drug-induced increase in cortical muscarinic acetylcholine receptor capacity might partly explain the cognition-enhancing and memory-improving effects of extracts from Withania somnifera observed in animals and humans. Title: Development of laminar expression of the m2 muscarinic cholinergic receptor gene in rat visual cortex and the effect of monocular visual deprivation Rossner S, Kumar A, Witzemann V, Schliebs R Ref: Brain Research Developmental Brain Research, 77:55, 1994 : PubMed ESTHER: Rossner_1994_Brain.Res.Dev.Brain.Res_77_55 PubMedSearch: Rossner 1994 Brain.Res.Dev.Brain.Res 77 55 PubMedID: 8131263 Abstract The postnatal development of laminar pattern of the m2 muscarinic acetylcholine receptor subtype mRNA in the visual cortex of both normally raised and monocularly deprived rats (one eyelid sutured at the age of 11 days) was studied using in situ hybridization histochemistry and computer-assisted image analysis. In normally raised rats, on birth, the m2 transcript was found to be more concentrated in the superficial zones of the cortex. This laminar pattern alters to a more homogeneous distribution of the label throughout the cortex already detectable on day 7. From day 10 onwards a bimodal laminar pattern gradually develops with increased mRNA levels in layer IV and upper layer VI. From postnatal day 21 onwards the hybridization peak in layer VI decreases as compared to the peak level in layer IV resulting in an adult distribution with highest labeling in layer IV, low labeling in layer I to III and moderate labeling in layers V and VI. Monocular deprivation results in decreased m2 mRNA levels in visual cortical layers IV-VI in both deprived and non-deprived cortices already detectable at the age of 18 days and persisting up to the age of 21 days; but this effect disappears following further deprivation until adulthood. The data suggest that the changes in m2 receptor level from a more homogeneous distribution to a bimodal pattern during postnatal development seem to be related to synaptogenesis and final tuning of connectional pattern within the rat visual cortex. Title: Clinico-biochemical use of serum acetylcholine esterase following treatment with synthetic pyrethroids, cypermethrin and fenvalerate, in cattle and buffalo experimentally infested with Boophilus microplus Ansari MZ, Kumar A, Prasad RL, Basu A, Sahai BN, Sinha AP Ref: Indian J Exp Biol, 28:241, 1990 : PubMed ESTHER: Ansari_1990_Indian.J.Exp.Biol_28_241 PubMedSearch: Ansari 1990 Indian.J.Exp.Biol 28 241 PubMedID: 2365420 Abstract Following treatment, cypermethrin and fenvalerate, were found to have inhibitory effect on serum acetylcholine esterase (AchE) activity of cattle and buffalo experimentally infested with B. microplus. The pattern of AchE activity in infested-pyrethroid-treated group was found to be significantly different from either healthy or tick-infested control. There was transient increase in the enzyme activity initially, followed by gradual decline and subsequent increase leading to normal level within 7 days of pyrethroid treatment. The enzyme activity was found to be low in buffalo than in cattle and the values remained below normal level up to day 7 in tick-infested group. The reversion of AchE activity to normal level in pyrethroid-treated group indicated that these compounds are prompt and safe ixodicides with least residual effect. The present investigation concludes that estimation of serum AchE might help in the clinico-biochemical diagnosis of tick toxin and pyrethroid toxicity in cattle and buffalo treated with these pyrethroids against tick infestation. | |||||||
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